Clin. Pharm. Card: SOLIQUA

SOLIQUA 100/33 (insulin glargine and lixisenatide injection), for subcutaneous use

 Sanofi-Aventis U.S. Bridgewater, NJ, USA

Image result for glp 1 receptor agonist

INDICATION:  Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus inadequately controlled on basal insulin (less than 60 units daily) or lixisenatide

Mechanism of Action SOLIQUA 100/33 is a combination of insulin glargine, a basal insulin analog, and lixisenatide, a GLP-1 (glucagon-like peptide-1) receptor agonist. The primary activity of insulin, including insulin glargine, is regulation of glucose metabolism. Insulin and its analogs lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis and proteolysis, and enhances protein synthesis. Lixisenatide increases glucose-dependent insulin release, decreases glucagon secretion, and slows gastric emptying.
Pharmacodynamics (PD) No impact of combination on  on the pharmacodynamics of insulin glargine. Impact of combination on PD  of lixisenatide has not been studied.

In adults with type 2 diabetes mellitus, lixisenatide reduced fasting plasma glucose and postprandial blood glucose AUC0–300mim compared to placebo (-33.8 mg/dL and -387 mg.h/dL, respectively) following a standardized test meal. The effect on postprandial blood glucose AUC was most notable with the first meal, and the effect was attenuated with later meals in the day. Treatment with lixisenatide 20 mcg once daily reduced postprandial glucagon levels (AUC0–300min) compared to placebo by -15.6 h.pmol/L after a standardized test meal in patients with type 2 diabetes.

At a dose 1.5-times the recommended dose, lixisenatide does not prolong the QTc interval to any clinically relevant extent.

Pharmacokinetics (PK) The insulin glargine/lixisenatide ratio has no relevant impact on the PK of insulin glargine in SOLIQUA 100/33.

Compared to administration of lixisenatide alone, the Cmax is lower whereas the AUC is generally comparable when administered as SOLIQUA 100/33. The insulin glargine/lixisenatide ratio has no impact on the PK of lixisenatide in SOLIQUA 100/33. The observed differences in the PK of lixisenatide when given as SOLIQUA 100/33 or alone are not considered to be clinically relevant.

 After subcutaneous administration of insulin glargine/lixisenatide combinations, insulin glargine showed no pronounced peak. Exposure to insulin glargine ranged from 86% to 101% compared to administration of insulin glargine alone.

After subcutaneous administration of insulin glargine/lixisenatide combinations, the median tmax of lixisenatide was in the range of 2.5 to 3.0 hours. There was a small decrease in Cmax of lixisenatide of 22–34% compared with separate simultaneous administration of insulin glargine and lixisenatide, which is not likely to be clinically significant. There are no clinically relevant differences in the rate.

 Protein binding of lixisenatide is 55%.

 Metabolism study in humans who received insulin glargine alone indicates that insulin glargine is partly metabolized at the carboxyl terminus of the B chain in the subcutaneous depot to form two active metabolites with in vitro activity similar to that of human insulin, M1 (21A-Gly-insulin) and M2 (21A-Gly-des-30B-Thr-insulin). Unchanged drug and these degradation products are also present in the circulation.

 Lixisenatide is presumed to be eliminated through glomerular filtration, and proteolytic degradation.

 After multiple dose administration in patients with type 2 diabetes, mean terminal half-life was approximately 3 hours and the mean apparent clearance (CL/F) about 35 L/h.

PK-PD Analysis No reported.
Population PK Age, body weight, gender, and race were not observed to meaningfully affect the pharmacokinetics of lixisenatide in population PK analyses,
Special Populations Effect of age, race, and gender on the pharmacokinetics of insulin glargine has not been evaluated. In controlled clinical trials in adults with insulin glargine (100 units/mL), subgroup analyses based on age, race, and gender did not show differences in safety and efficacy.

 Compared to healthy subjects (N=4), plasma Cmax of lixisenatide was increased by approximately 60%, 42%, and 83% in subjects with mild (CLcr 60–89 mL/min [N=9]), moderate (CLcr 30–59 mL/min [N=11]), and severe (CLcr 15–29 mL/min [N=8]) renal impairment. Plasma AUC was increased by approximately 34%, 69% and 124% with mild, moderate and severe renal impairment, respectively.

Drug Interactions Due to their peptidic nature, insulin glargine and lixisenatide have no relevant potential to induce or inhibit CYP isozymes and therefore, no direct drug interaction is expected.

 Interaction studies performed with the individual components. 

Lixisenatide did not change the overall exposure (AUC) of acetaminophen following administration of a single dose of acetaminophen 1000 mg, whether before or after lixisenatide. No effects on acetaminophen Cmax and tmax were observed when acetaminophen was administered 1 hour before lixisenatide. When administered 1 or 4 hours after 10 mcg lixisenatide, Cmax of acetaminophen was decreased by 29% and 31%, respectively, and median tmax was delayed by 2.0 and 1.75 hours, respectively.

 Administration of a single dose of an oral contraceptive medicinal product (ethinylestradiol 0.03 mg/levonorgestrel 0.15 mg) 1 hour before or 11 hours after 10 mcg lixisenatide, did not change Cmax, AUC, t1/2 and tmax of ethinylestradiol and levonorgestrel. Administration of the oral contraceptive 1 hour or 4 hours after lixisenatide did not affect the AUC and mean terminal half-life (t1/2) of ethinylestradiol and levonorgestrel. However, Cmax of ethinylestradiol was decreased by 52% and 39%, respectively, and Cmax of levonorgestrel was decreased by 46% and 20%, respectively, and median tmax was delayed by 1 to 3 hours.

 When lixisenatide 20 mcg and atorvastatin 40 mg were coadministered in the morning for 6 days, the exposure of atorvastatin was not affected, while Cmax was decreased by 31% and tmax was delayed by 3.25 hours. No such increase for tmax was observed when atorvastatin was administered in the evening and lixisenatide in the morning but the AUC and Cmax of atorvastatin were increased by 27% and 66%, respectively.

 After concomitant administration of warfarin 25 mg with repeated dosing of lixisenatide 20 mcg, there were no effects on AUC or INR (International Normalized Ratio) while Cmax was reduced by 19% and tmax was delayed by 7 hours.

 After concomitant administration of lixisenatide 20 mcg and digoxin 0.25 mg at steady state, the AUC of digoxin was not affected. The tmax of digoxin was delayed by 1.5 hour and the Cmax was reduced by 26%.

 After concomitant administration of lixisenatide 20 mcg and ramipril 5 mg during 6 days, the AUC of ramipril was increased by 21% while the Cmax was decreased by 63%. The AUC and Cmax of the active metabolite (ramiprilat) were not affected. The tmax of Ramipril and ramiprilat were delayed by approximately 2.5 hours.



Clin. Pharm. Card: AMJEVITA

AMJEVITA (adalimumab-atto) injection for subcutaneous use

Biosimilar to HUMIRA (adalimumab

Image result for humira mechanism of action


Rheumatoid Arthritis : Reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function

Juvenile Idiopathic Arthritis: Reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis

Psoriatic Arthritis: Reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis

Ankylosing Spondylitis : Reducing signs and symptoms in adult patients with active ankylosing spondylitis

Adult Crohn’s Disease: Reducing signs and symptoms and inducing and maintaining clinical remission

Ulcerative Colitis: Inducing and sustaining clinical remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants

Plaque Psoriasis: Treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy

Mechanism of Action Adalimumab products bind specifically to TNF-alpha and block its interaction with the p55 and p75 cell surface TNF (tumor necrosis factors) receptors. Adalimumab products also lyse surface TNF expressing cells in vitro in the presence of complement. Adalimumab products do not bind or inactivate lymphotoxin (TNF-beta). TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels of TNF are found in the synovial fluid of patients with RA (Rheumatoid Arthritis), JIA (Juvenile Idiopathic Arthritis), PsA (Psoriatic Arthritis), and AS (Ankylosing Spondylitis) and play an important role in both the pathologic inflammation and the joint destruction. Increased levels of TNF are also found in psoriasis plaques (Ps). In Ps, treatment with AMJEVITA may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which adalimumab products exert their clinical effects is unknown. Adalimumab products also modulate biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X10-10 M).
Pharmacodynamics (PD) After treatment with adalimumab, a decrease in levels of acute phase reactants of inflammation (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was observed compared to baseline in patients with RA. A decrease in CRP levels was also observed in patients with Crohn’s disease (CD) and ulcerative colitis (UC). Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodeling responsible for cartilage destruction were also decreased after adalimumab administration.
Pharmacokinetics (PK) The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) with adalimumab treatment were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects.

 The average absolute bioavailability of adalimumab estimated following a single 40 mg subcutaneous dose was 64%.

 The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. The single dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg.

 The distribution volume (Vss) ranged from 4.7 to 6.0 L. The systemic clearance of adalimumab is approximately 12 mL/hr. The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies.

 Adalimumab concentrations in the synovial fluid from five rheumatoid arthritis patients ranged from 31 to 96% of those in serum.

In RA patients receiving 40 mg adalimumab every other week, adalimumab mean steady-state trough concentrations of approximately 5 μg/mL and 8 to 9 μg/mL, were observed without and with methotrexate (MTX), respectively. MTX reduced adalimumab apparent clearance after single and multiple dosing by 29% and 44% respectively, in patients with RA. Mean serum adalimumab trough levels at steady state increased approximately proportionally with dose following 20, 40, and 80 mg every other week and every week subcutaneous dosing. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time.

 Adalimumab mean steady-state trough concentrations were slightly higher in psoriatic arthritis patients treated with 40 mg adalimumab every other week (6 to 10 μg/mL and 8.5 to 12 μg/mL,without and with MTX, respectively) compared to the concentrations in RA patients treated with the same dose.

 The pharmacokinetics of adalimumab in patients with AS were similar to those in patients with RA.

In patients with CD, the loading dose of 160 mg adalimumab on Week 0 followed by 80 mg adalimumab on Week 2 achieves mean serum adalimumab trough levels of approximately 12 μg/mL at Week 2 and Week 4. Mean steady-state trough levels of approximately 7 μg/mL were observed at Week 24 and Week 56 in CD patients after receiving a maintenance dose of 40 mg adalimumab every other week.

 In patients with UC, the loading dose of 160 mg adalimumab on Week 0 followed by 80 mg adalimumab on Week 2 achieves mean serum adalimumab trough levels of approximately 12 μg/mL at Week 2 and Week 4. Mean steady-state trough level of approximately 8 μg/mL was observed at Week 52 in UC patients after receiving a dose of 40 mg adalimumab every other week, and approximately 15 μg/mL at Week 52 in UC patients who increased to a dose of 40 mg adalimumab every week.

In patients with Ps, the mean steady-state trough concentration was approximately 5 to 6 μg/mL during adalimumab 40 mg every other week monotherapy treatment.

Minor increases in apparent clearance were also predicted in RA patients receiving doses lower than the recommended dose and in RA patients with high rheumatoid factor or CRP concentrations. These increases are not likely to be clinically important.

PK-PD Analysis                    No reported.
 Population PK Population pharmacokinetic analyses in patients with RA revealed that there was a trend toward higher apparent clearance of adalimumab in the presence of anti-adalimumab antibodies, and lower clearance with increasing age in patients aged 40 to > 75 years.


Special Populations No gender-related pharmacokinetic differences were observed after correction for a patient’s body weight. Healthy volunteers and patients with rheumatoid arthritis displayed similar adalimumab pharmacokinetics.

 No pharmacokinetic data are available in patients with hepatic or renal impairment.

 In study with polyarticular JIA patients who were 4 to 17 years of age, the mean steady-state trough serum adalimumab concentrations for patients weighing < 30 kg receiving 20 mg adalimumab subcutaneously every other week as monotherapy or with concomitant MTX were 6.8 μg/mL and 10.9 μg/mL, respectively. The mean steady-state trough serum adalimumab concentrations for patients weighing ≥30 kg receiving 40 mg adalimumab subcutaneously every other week as monotherapy or with concomitant MTX were 6.6 μg/mL and 8.1 μg/mL, respectively.

PD Interactions  In RA patients, increased risk of serious infections has been seen with the combination of TNF blockers with anakinra or abatacept, with no added benefit

Higher rate of serious infections RA patients treated with rituximab with subsequent treatment with a TNF blocker

The formation of CYP450 enzymes may be suppressed.



Clin. Pharm. Card: INTRAROSA

INTRAROSA (prasterone) vaginal inserts

Related image

 INDICATION: Steroid indicated for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause. 

Mechanism of Action Prasterone is an inactive endogenous steroid and is converted into active androgens and/or estrogens. The mechanism of action of INTRAROSA in postmenopausal women with vulvar and vaginal atrophy is not fully established.
Pharmacodynamics (PD) Not reported.
Pharmacokinetics (PK) In a study conducted in postmenopausal women, administration of the INTRAROSA vaginal insert once daily for 7 days resulted in a mean prasterone Cmax and area under the curve from 0 to 24 hours (AUC0- 24) at Day 7 of 4.4 ng/mL and 56.2 ngh/mL, respectively, which were significantly higher than those in the group treated with placebo.

 The Cmax and AUC0- 24 on Day 7 of the testosterone metabolite (metabolite of prasterone) were 0.15 ng/mL and 2.79 ngh/mL, respectively which were slightly higher in women treated with the INTRAROSA vaginal insert compared to those receiving placebo, 0.12 ng/mL and 2.58 ngh/mL, respectively.

 The Cmax and AUC0- 24 on Day 7 of the estradiol metabolite (metabolite of prasterone) were 5.04 pg/mL and 96.93 pgh/mL, respectively which were also slightly higher in women treated with the INTRAROSA vaginal insert compared to those receiving placebo, 3.33 pg/mL and 66.49 pgh/mL, respectively.

 Exogenous prasterone is metabolized in the same manner as endogenous prasterone. Human steroidogenic enzymes such as hydroxysteroid dehydrogenases, 5α-reductases and aromatases transform prasterone into androgens and estrogens.

 In two primary efficacy trials, daily administration of INTRAROSA vaginal insert for 12 weeks increased mean serum Ctrough of prasterone and its metabolites testosterone and estradiol by 47%, 21% and 19% from baseline, respectively. This comparison based on Ctrough may underestimate the magnitude of increase in prasterone and metabolites’ exposure because it does not take into account the overall concentration-time profile following administration of INTRAROSA.

PK-PD Analysis                          Not reported.
Population PK Not reported.
 Special Populations  Not reported.
Drug Interactions Not reported.


Clin. Pharm. Card: EXONDYS 51

EXONDYS 51 (Eteplirsen) intravenous injection

Sarepta Therapeutics, Inc. Cambridge, MA, USA

Image result for EXONDYS 51 (Eteplirsen) image

INDICATION: Treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. Approved under accelerated approval based on an increase in dystrophin in skeletal muscle observed in some patients treated with EXONDYS 51

Mechanism of Action Binds to exon 51 of dystrophin pre-mRNA (messenger ribonucleic acid), resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 51 skipping. Exon skipping is intended to allow for production of an internally truncated dystrophin protein.
Pharmacodynamics (PD) All EXONDYS 51 treated patients evaluated (n=36) were found to produce mRNA for a truncated dystrophin protein by reverse transcription polymerase chain reaction.

 In Study 2, the average dystrophin protein level in muscle tissue after 180 weeks of treatment with EXONDYS 51 was 0.93% of normal (i.e., 0.93% of the dystrophin level in healthy subjects). Because of insufficient information on dystrophin protein levels before treatment with EXONDYS 51 in Study 1, it is not possible to estimate dystrophin production in response to EXONDYS 51 in Study 1.

 In Study 3, the average dystrophin protein level was 0.16% of normal before treatment and 0.44% of normal after 48 weeks of treatment with EXONDYS 51. The median increase in truncated dystrophin in Study 3 was 0.1%.           

Pharmacokinetics (PK) Single or multiple intravenous infusions lead to the peak plasma concentrations (Cmax) of eteplirsen occurring near the end of infusion (i.e., 1.1 to 1.2 hours across a dose range of 0.5 mg/kg/week to 50 mg/kg/week).

Following single or multiple intravenous infusions in male pediatric DMD patients, plasma concentration-time profiles of eteplirsen were generally similar and showed multi-phasic decline.

 The majority of drug elimination occurred within 24 hours.

 Approximate dose-proportionality and linearity in PK properties were observed following multiple-dose studies (0.5 mg/kg/week [0.017 times the recommended dosage] to 50 mg/kg/week [1.7 times the recommended dosage]). There was no significant drug accumulation following weekly dosing across this dose range. The inter-subject variability for Cmax and AUC range from 20 to 55%, respectively.

Plasma protein binding (in vitro) in human ranges between 6 to 17%. The mean apparent volume of distribution (Vss)  was 600 mL/kg following weekly intravenous infusion of EXONDYS 51 at 30 mg/kg.

 Total clearance is 339 mL/hr/kg following 12 weeks of therapy with 30 mg/kg/week. Renal clearance accounts for approximately two-thirds of the administered dose within 24 hours of intravenous administration.

 Elimination half-life (t1/2) is 3 to 4 hours. 

PK-PD Analysis Not reported.
Population PK Not reported.
 Specific Populations  Effect of age (65 years or older), sex, race or renal/hepatic Impairment was not reported.
 Drug Interactions  In vitro studies showed that eteplirsen did not significantly inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5. Eteplirsen did not induce CYP2B6 or CYP3A4, and induction of CYP1A2 was substantially less than the prototypical inducer, omeprazole. Eteplirsen was not a substrate nor did it have any major inhibitory potential for any of the key human transporters tested (OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, P-gp, BCRP, MRP2 and BSEP). Based on in vitro data on plasma protein binding, CYP or drug transporter interactions, and microsomal metabolism, eteplirsen is expected to have a low potential for drug-drug interactions in humans.






Webinar – Final Guidance on Medical Device Reporting for Manufacturers



Reporting requirements for:

  • Manufacturer
  • Device user facilities
  • Importers

Reporting of:

  • Death
  • Serious injury
  • Malfunctions

Reporting Followups:

  • Complete investigation of each event
  • Develop & Implement reporting procedures
  • Establish & Maintain reporting files
  • Create system for expedited information access for follow-up/FDA inspection




FDA Debrief: CDRH Veteran Amputee Device Workshop, October 31, 2016


KEY Concepts

  • Use / Assess TPLC (Total Product Life Cycle)
  • Engagement to improve patient experience – better understand patient preference and patient input
  • Include amputee preference in B/R assessment

DR. VIVEK PINTO:  Branch Chief, PMDB

  • Non-invasive prosthetic devices are generally Class I Exempt devices
  • Must comply with general controls: Components for prosthetic limbs, Assembled systems
  • TPLC
    • Novel prosthetics – less knowledge about safety and effectiveness : Greater premarket purview
    • Customary prosthetics- history of safety and effectiveness – Greater postmarket purview


  • Functional Outcome measures
  • Patient-centered, Clinically-meaningful test methods
  • DARPA haptics, VR platform 


  • IoT/Interoperability: Data/Specification? Include in label what is / is not compatible
  • Differences in classification of ‘similar’ devices: FR publishes reviews, FDA will note to increase transparency
  • Patients vs Physician measures of performance: Website for tests used by physicians?
  • Lack of readily available information of approves/cleared prosthetics
  • Johns Hopkins University Patient Preference methods: Incorporate patient & caregiver voice : Facts vs Values, Measuring choices
  • LIM innovations: Optimal Socket design , R&D approach to incorporate user feedback: Improve comfort stds, Understanding patient journey post-amputation, connected tech to prosthetics, moderated interviews
  • FDA-CMS considerations upfront

VA Amputation Society (ASoc) Clin perspectives on amputation care

    • Enhance quality and consistency of amputation care
    • Prosthetic dissatisfaction and abandonment
    • Tech advances outpaces research

Prosthesis prescription considerations

  • Must be based on the Veteran not the available technology
  • Prosthetic education and training essential to successful outcomes
  • Greater need for highly specialized teams with advanced technology


CDRH Industry Basics: Quality System & Management Controls

November 3, 2016




Management is Core – ultimately responsible for entire Quality System (QS)

  • Involved, Engaged and Committed to the QS
  • Senior Employee with executive responsibilities
  • Harmonized with ISO and other global regulations

Implement Management Control Subsystem

  • Adequate resources
  • Ensure adequate and effective QS
  • Monitor QS and make necessary adjustments

Management Responsibilities to Establish & Maintain

  • Quality Policy
  • Effective organization structure
  • Appropriate responsibility and authority
  • Adequate resources
  • Appoint representatives
  • Management reviews
  • Establish Quality Plan
  • Establish QS Procedures

Conduct Internal Audit

  • Appropriate auditor, appropriate steps to address issues
  • Appropriate documentation


  • With appropriate qualifications, training, background











  1. A way to send information to FDA
  2. A way to get safety information from FDA
  • Who, How, When What to report
  • High Quality Report Authoring : Tutorials, practices
  • Facilitated reporting: Online, Mail/Fax, Phone, Mobile

FDA Review and Actions from Reports : Signal Detection based on reports, Safety communications, Labeling changes

Resources :



FDA Webinar on Patient Preference Information





  • Provide context and overview of Patient Preference Information Final Guidance
  • Describe key updates to the Benefit-Risk worksheet in the “Factors to Consider When Making Benefit-Risk Determinations in Medical Device Premarket Approval and De Novo Classifications” Guidance
  • Differences between Patient Preference vs. patient Reported Outcome


FDA Webinar Debrief : Neurological Devices




Key Takehomes
– New Division
– Design studies based on Indication for Use and Label claims
– Time studies based on your product roadmap
–  Keep documentation and assess impact of product design changes
– IRBs can be a helpful resource for IDE waivers
– Early Feasibility Studies (EFS) encouraged for streamlined development
– Several options of getting in touch directly with Division


Clinical Pharmacology Cards: JADENU, SYNJARDY



Image result for JADENU


Mechanism of Action


Orally active chelator that is selective for iron (as Fe3+) for the treatment of chronic iron overload due to blood transfusions.
Pharmacodynamics (PD)





Deferasirox (10, 20,and 40 mg per kg per day) was able to induce a mean net iron excretion (0.119, 0.329,and 0.445 mg Fe/kg body weight per day, respectively) within the clinically relevant range (0.1 to 0.5 mg per kg per day). Iron excretion was predominantly fecal.

The effect of 20 and 40 mg per kg per day of deferasirox (tablets for oral suspension) as single dose showed no evidence of prolongation of the QTc interval.

Pharmacokinetics (PK)













Linear PK with mean elimination half-life ranged from 8 to 16 hours and mean steady state volume of distribution was of 14.37 L. The absolute bioavailability (AUC) of deferasirox tablets for oral suspension was 70%. The bioavailability of JADENU was 36% greater than with deferasirox tablets for oral suspension.

AUC and Cmax were slightly decreased after a low-fat meal (by 11% and 16%, respectively). After a high-fat meal, AUC and Cmax were increased by 18% and 29%, respectively. It is recommended that JADENU should be taken on an empty stomach or with a light meal.

Females have a moderately lower apparent clearance (by 17.5%) for deferasirox compared to males.

Deferasirox is highly (~99%) protein bound almost exclusively to serum albumin.

Deferasirox and metabolites are primarily (84% of the dose) excreted in the feces. Renal excretion of deferasirox and metabolites is minimal (8% of the administered dose).

Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3.

PK-PD Analysis Not reported
Population PK Not reported
Special Populations





Compared to patients with myelodysplastic syndrome (MDS) and CLCr greater than 60 mL/min, patients with MDS and CLCr 40 to 60 mL/min had approximately 50% higher mean deferasirox trough plasma concentrations.

In children less than 6 years of age, systemic exposure was about 50% lower than in adults, However, the safety and efficacy of deferasirox in pediatric patients was similar to that of adult patients.

Drug Interactions





Deferasirox may induce CYP3A4 and inhibit CYP2C8 and CYP1A2.

The concomitant use of JADENU with potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) may result in a decrease in JADENU efficacy due to a possible decrease in deferasirox concentration. Avoid the concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol) with JADENU due to a possible decrease in deferasirox concentration.



Image result for synjardy

Mechanism of Action







SYNJARDY combines 2 antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and metformin, a member of the biguanide class.

Empagliflozin, by inhibiting SGLT2, reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

Pharmacodynamics (PD)







In patients with type 2 diabetes, urinary glucose excretion increased immediately following a dose of empagliflozin and was maintained at the end of a 4-week treatment period averaging at approximately 64 grams per day with 10 mg empagliflozin and 78 grams per day with 25 mg empagliflozin once daily.

In a 5-day study, mean 24-hour urine volume increase from baseline was 341 mL on Day 1 and 135 mL on Day 5 of empagliflozin 25 mg once daily treatment.

No increase in QTc was observed with either 25 mg or 200 mg empagliflozin.

Pharmacokinetics (PK)

























SYNJARDY (empagliflozin/metformin hydrochloride) 5 mg/500 mg, 5 mg/1000 mg, 12.5 mg/500 mg, and 12.5 mg/1000 mg combination tablets are bioequivalent to coadministration of corresponding doses of empagliflozin and metformin as individual tablets.

Systemic exposure of empagliflozin increased in a dose-proportional manner in the therapeutic dose range. The single-dose and steady-state pharmacokinetic parameters of empagliflozin were similar, suggesting linear pharmacokinetics with respect to time.

There is a lack of dose proportionality with increasing Metformin doses, which is due to decreased absorption rather than an alteration in elimination. Plasma and blood elimination half-lives of Metformin are approximately 6.2 and 17.6 hours, respectively. The apparent volume of distribution of metformin following single oral dose of immediate-release metformin hydrochloride tablets 850 mg averaged 654±358 L.

Food has no clinically relevant effect on AUC or Cmax of empagliflozin or metformin.

Empagliflozin partitioned approximately 36.8% to red blood cell. Its plasma protein binding was 86.2%. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas (SUs), which are more than 90% protein bound.

Systemic exposure of each of 3 glucuronide conjugate metabolites of empagliflozin was less than 10% of total drug-related material.

Metformin excretes as unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion.

The majority of drug-related radioactivity recovered in feces was unchanged empagliflozin and approximately half of drug-related radioactivity excreted in urine was unchanged empagliflozin.

Renal clearance of metformin is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. The change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.

PK-PD Analysis Not reported
Population PK




The apparent steady-state volume of distribution of empagliflozin was estimated to be 73.8 L. The apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 h and apparent oral clearance was 10.6 L/h based on the population pharmacokinetic analysis.

Body mass index, gender and race do not have a clinically meaningful effect on pharmacokinetics of empagliflozin.

Special Populations






Age did not have a clinically meaningful impact on the pharmacokinetics of empagliflozin

In subjects with mild, moderate, and severe hepatic impairment according to the Child-Pugh classification, AUC of empagliflozin increased by approximately 23%, 47%, and 75%, and Cmax increased by approximately 4%, 23%, and 48%, respectively.

In healthy elderly subjects, the total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased.

Drug Interactions





PK drug interaction studies with SYNJARDY have not been performed; however, such studies have been conducted with the individual components empagliflozin and metformin.  No dose adjustment of empagliflozin is recommended when coadministered with commonly prescribed medicinal products based on results of the described PK studies.

Empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin.





Mechanistic Oral Absorption Modeling and Simulation

Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation


FDA Public Workshop was hosted on May 19, 2016 by the US Food and Drug Administration (FDA) at its White Oak Campus in Silver Spring, MD. The workshop speakers were from the FDA, industry, and academia. The workshop was chaired by Dr. Liang Zhao, Director of Division of Quantitative Methods & Modeling Office of Research Standards Office of Generic Drugs.

The plenary sessions presenters were from FDA (Drs. John Duan, Xinyuan Zhang,  from industry (Drs. Filippos Kesisoglou (Merck), Jasmina Novakovic (Apotex ), Masoud Jamei  (Simcyp), Viera Lukacova (SimulationsPlus) and Thomas Eissing (Bayer Technology), and from academia (Dr. Gordon Amidon, University of Michigan).  Dr. Kathleen Uhl gave the opening remarks and Dr. Robert Lionberger gave the closing remarks.

A few Dr. Zhao’s presentation slides were on:

  • M&S Impact Various Regulatory Activities in OGD (4/1/15 to 4/1/16)
  • PBPK in Applications for Generics
  • Number of Compounds Assessed Using Absorption Modeling
  • PBPK Applications in NDA: Current Status
  • Drug labels with dosing recommendations informed by PBPK

Dr. Duan’s presentation title was The Application of Mechanistic Oral Absorption Model in Biopharmaceutics Review”. Highlights of presentation were:

His presentation outline slide described an overview, covering

  • Patient first initiative in drug development
  • Biopharmaceutics Team growth
  • Predictions help decision making

Current status, covering

  • Current practice
  • Dissolution spec setting
  • Set clinically relevant product specs
  • Risk assessment

PBPK Future App

  • Meet the challenge
  • Information in regulatory submission
  • Product life cycle management

Dr. Zhang’s presentation title was OGD Experience and Efforts on Oral Absorption Modeling and Simulation”. Highlights of presentation were:

Update on Absorption Modeling and Simulation in OGD

  • Innovative Model for Future Product Development

Case Examples:

  • Evaluate the impact of slow dissolution in a specific pH condition on BE (warfarin sodium tablets)
  • Evaluate the PPI impact on BE (prasugrel HCl tablets, fingolimod capsules)

Summary slides had following points:

  • OGD has routinely applied mechanism-based absorption modeling and simulation to address various issues raised in regulatory activities.
  • OGD is actively improving the science of predictions for oral solid dosage forms.
  • OGD is willing to collaborate with internal and external stakeholders to advance the application of mechanism-based absorption modeling and simulation in drug product development and regulatory review.

Dr. Kesisoglou’s presentation title was Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation: An Industry Perspective”. A few presentation slides were on:

  • Current status of absorption modeling in formulation development
  • Case studies
    • Formulation development and achlorhydric simulations
    • Dissolution impact on PK and BE projections
    • Multimedia dissolution and BE projections
    • Projection of API form change and population simulations
    • Food effect projection for a BCS I compound
    • Absorption modeling-based IVIVC for IR tablet
    • Conclusions and future directions

Dr. Novakovic’s presentation title was ”Modeling and Simulations for Development and Bioequivalence Evaluation of a Generic Drug Product”. Highlights of presentation were:

Roles of PBPK modeling and simulation

Early development

  • Reference List Drug (RLD) characterization;
  • Establishing Quality Target Product Profile (QTPP);
  • Formulation design and product development of to achieve bioequivalence

Life-cycle and Quality Risk Management (QRM)

  • Bio-indicative dissolution test conditions and clinically meaningful specification limits;
  • Bio-study waiver for the additional strengths and SUPAC;
  • Critical material attributes (CMA) and boundaries for a rate–controlling excipient;

Summary slide had the following points:

  • At early product development stage PBPK modeling is a proven toll to characterize RLD, facilitate product development to define formulation strategy and achieve bioequivalence;
  • During life-time cycle management, QRM is ensured by implementing adequate controlled strategies (i.e. test methods and specification limits);
  • Controlled strategy, established to ensure BE, is developed based on PBPK modeling;
  • PBPK Modeling and Simulation is a powerful but underused tool to facilitate development and ensure QRM of a generic drug product.

Dr. Amidon’s  presentation title was ” Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence (BE) Evaluation ”.

Dr. Jamei presentation title was ” Mechanistic Modeling and Simulation of Oral Drug Absorption: Opportunities and Challenges”. A few presentation slides were on:


IVIVE (in vitro-in vivo extrapolation )-Linked PBPK absorption modelling

Physiologically-based IVIVC (PB-IVIVC)

Bioequivalence and PBPK modelling

Dr. Lukacova’s presentation title was ”Incorporating Mechanistic Modeling & Simulation to Assist with Formulation Development”. Highlights of presentation were:


  • Why Modeling & Simulation?
  • Overview of Mechanistic Simulation Models
  • Predicting in vivo absorption & PK

Applications in Generic Product Development

  • Generating IVIVCs
  • Performing virtual bioequivalence trials and establishing dissolution specifications
  • Understanding food effects

A successful biowaiver case study


Summary slide was:

  • A mechanistic, physiologically-based absorption/PK model was constructed in GastroPlus and validated across three dose levels (50, 100, and 300 mg) using in vivo data collected from tablets manufactured with non-particle-engineered API.
  • Parameter sensitivity analysis showed that mean particle size would be the main property that determines whether formulations are likely to be bioequivalent, regardless of dose.
  • Virtual bioequivalence trial simulations showed that, for a sufficiently powered study, the population-derived Cmax and AUC values would be bioequivalent between the tablets manufactured with non-particle-engineered (NPE) vs. new-particle-engineered (PE) API, regardless of the dose.
  • Regulatory agencies approved the sponsor’s biowaiver application

Dr. Eissing’s  presentation title was ” PK-Sim for Mechanistic Oral Absorption Modeling and Simulation and More”. A few presentation slides were on:

  • Introduction: PBPK modeling with PK-Sim & MoBi
  • Oral absorption and dissolution modeling
    • Concept
    • Examples
    • Implementation


  • Examples shown for how to model different formulations and their oral absorption in PK-Sim/MoBi to better understand PK
  • PK-Sim is a PBPK tool with a focus on flexibility and transparency, together with MoBi leaving a lot of room for problem specific solutions

Dr. Kesisoglou’s presentation title was ”OrBiTo: Innovative Tools for Oral Biopharmaceutics”. Highlights of presentation were:


  • Programme vision, mission and objectives
  • Members of the OrBiTo consortium
  • OrBiTo Work Packages
    • Aims and deliverables
    • Highlights of progress to date
  • Integration of dissolution in PBPK models

Objective slide described:

  • Define the critical physicochemical, formulation and physiological factors that determine oral drug product performance.
  • Develop both experimental and theoretical models which can be used to robustly predict the in vivo performance of formulated drug products.
  • Fully leverage industrial knowledge and experience through pooling existing physicochemical, in vitro characterization, preclinical and clinical data to assess the reliability of currently available prediction methods and to underpin the development of new modelling and simulation tools.

Physicochemical tools – Understanding the API


  1. Provide a range of in vitro physico-chemical tools and in silico models that can assess the API’s key molecular properties important for in vivo performance, including excipient interactions
  2. Provide the information gained by use of tools, defined in objective 1, for a subset of the OrBiTo database to establish a Drug Development Decision Tree, expanding the DCS and facilitating drug formulation selection and optimising the dosage form design process
  3. Integrate knowledge and results obtained from physico-chemical studies and models in WP1 with “In vitro tools – understanding the formulation” (WP2).
  4. Serve as physico-chemical parameter input for integrated modelling and predictive tools developed in WP4 (PBPK modelling).


Debrief: Patient-Focused Drug Development for Neuropathic Pain Associated with Peripheral Neuropathy


Opening Remarks

Pamela Horn, MD Medical Officer Team Lead, DAAAP, CDER, FDA

  • Meeting addresses an unmet need for treatment that is finding patient-centered endpoints for clinical trials.
  • Hearing from patients will help steer drug development
  • FDA works to ensure safety, effectiveness, and quality of drugs

Overview of FDA’s Patient-Focused Drug Development Initiative

Sara Eggers, PhD OSP, CDER, FDA

  • Goal is to make more systematic way to gether patients inputs and perspectives
  • Originated from PDUFA V
  • This meeting is the 19th of 24 PFDD meetings for FY 2013-2017
  • Active patient involvement and participation encouraged

Background on Pain Neuropathies and Available Treatments

Steven Galati, MD, Medical Officer, DAAAP, CDER, FDA

  • Chronic Pain can be nociceptive (injury/inflammation) or neuropathic (pain without a stimulus)
  • Many different causes of neuropathy including diabetes and medical treatment
  • For the FDA to approve a neuropathy drug, there must be at least two successful trials
  • The FDA wants to know what symptoms bother patients the most so companies can target them in trials
  • Some challenges to drug development are that patients are still not satisfied with the drug and that one medication cannot cover multiple types of neuropathy

The Road from PFDD Meetings to Clinical Trial Endpoints

Nikunj Patel, PharmD Clinical Outcomes Assessments Staff, CDER, FDA

  • Patient recorded outcomes (such as answers to a questionnaire) will help create clinical trial endpoints
  • Stakeholders can listen to patients’ perspectives
  • PFDD meetings ensure that PRO’s accurately describe efficacy and drug safety
  • FDA encourages audience to engage others outside of PFDD meetings for more input
  • 3 pathways to generate outcome assessments
    • Input during investigational new drug submissions
    • Clinical outcome assessments (COA’s) to prove a treatment’s benefit during trials
    • Critical Path Innovation Meetings to advance drug efficacy using input from industry, academia, and patient-related groups

Panel #1 Discussion on Topic 1: Disease Symptoms and Daily Impacts

Adam Halper

    • Symptoms including soreness/muscle heaviness vary in intensity based on how much activity he does
    • Other symptoms including burning sensations are not “activity-dependent”
    • Limited mobility and cannot stand for more than 10-30 minutes
    • On worst days, can walk for only 5 minutes and cannot sleep comfortably
    • On best days, can walk about 3 miles
    • Intensity of symptoms fluctuates (no clear progression)

Susan Waldrop

    • Condition resulted from chemotherapy for colon cancer
    • Experiences burning sensations in limbs, electric shocks, and cannot walk, unpleasant numbness, increased sensitivity to cold
    • She cannot feel feet, causing problems with balance
    • Good days of normal activity are followed by bad nights

David Morrow (VP, Neuropathy Support Network)

    • Also resulted from chemotherapy for colon cancer
    • Slow progression
    • Experiences some foot and hand numbness, stabbing pains in feet, balance problems
    • Symptoms became less noticeable over time

Beth Lannon

    • Began as bilateral pain and slowly progressed
    • Sharp, constant pain (“like a hammer to my feet”), electrical shocks
    • Symptoms worsen with activity
      • Cannot sit for more than 15 minutes

Panel #2 Discussion on Topic #2: Current Approaches to Treatment

Linda Spinella

    • Pain because of multiple herniated disks
    • Was prescribed Lyrica, OTC pain relievers (incl. Tylenol), Prednisolone, opiods
    • Also went to the chiropractor and received epidurals for short-term relief
    • Cannot sleep without medication
    • Usually anxious, jittery, agitated

Cherie Pagett

    • Experiences numbness up to her knees
    • Takes Neurontin, Miradol, Lidocaine, opioids
    • When she took Lyrica, she gained 25 pounds in six weeks
    • Does not feel that her pain is under control because she will have intense flashes of pain

Louis Schmitt

    • 20 months of high dosage of IVIG to repair damaged nerves
    • Believes meditation managed anxiety/depression associated with his neuropathy
    • Prescribed 4000 mg neurontin but it did not work
    • Feels that 450 mg Lyrica is a “life saver” because it gives almost immediate relief
    • Tries to exercise as often as he can
    • Brain feels lagged (“mental fog”),
    • Experiences drowsiness, weight fluctuations, and swelling
    • If he were in a clinical trial, he would like to know of all side effects ahead of time and any estimate of effectiveness

Jackie Evangelista

    • Neuropathy caused by lyme disease
    • Slow progression of disease to the point that she cannot notice the worsening f some symptoms
    • Condition has not improved that much from medication
      • Feels treatment “only takes the edge off… does not stop advance”

Large-Group Facilitated Discussion: Topic 2

  • Trials should measure how much time one can do a specific physical task
  • Some patients feel that just pain relief is not the best indicator for drug effectiveness
  • Patients usually try a treatment for 3-4 weeks before deciding if it works
  • The issue of side effects is the most prevalent causing of switching medications/therapies
  • Some patients feel that support groups, meditation, and other activities to boost emotional well being help diminish the effect of pain


Addressing Statin Intolerance



High LDL-C (low-density lipoprotein – cholesterol or hypercholesterolemia) is a significant risk factor for cardiovascular disease. The CDC (Centers for Disease Control) through NHANES (National Health & Nutrition Examination Survey) estimated that over 81 million U.S. adults have elevated levels of LDL-C. In the U.S., increasing attention has been placed on aggressive LDL-C lowering.

This has led to the combination of statins with other treatments to reach LDL-C goals. Statins which includes such brand names as Lipitor, Zocor, Pravachol, Crestor, Livalo and others have been shown to be effective in reducing LDL-C and consistently have been shown to be associated in reduction in heart and vascular disease risk. The most common side effects of statins include gastrointestinal intolerance such as constipation, nausea, or indigestion, headache and upper respiratory type symptoms.

However, a subset of patients is unable to tolerate statins due to side effects, including muscle pain or weakness (Myalgia), increased glucose levels and increased liver transaminase.  In 2012, the FDA warned that statins can cause hyperglycemia (an increase in blood sugar levels) and increased the risk of worsening of glycemic control and of new onset diabetes.


A new class of cholesterol drug could sharply cut bad LDL cholesterol in people who cannot tolerate the commonly used cholesterol-lowering medications called statins.

Praluent (alirocumab injection) and Repatha (evolocumab injection) are PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors. PCSK9 inhibitors work by blocking a protein in the liver that helps regulate LDL. These drugs are for use in addition to diet and maximally tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia (HeFH) or patients with clinical atherosclerotic cardiovascular disease such as heart attacks or strokes, who require additional lowering of LDL cholesterol. HeFH is an inherited condition that causes high levels of LDL cholesterol.

Kynamro (mipomersen sodium injection) is a first-in-class antisense oligonucleotide (ASO) inhibitor targeted to apolipoprotein B-100 (apoB-100). Mipomersen’s proposed indication is as an adjunct to maximally tolerated lipid-lowering medications and diet to reduce low-density lipoprotein (LDL-C), apoB, total cholesterol, non-high-density-lipoprotein-cholesterol (non-HDL) and lipoprotein (a) in individuals with homozygous familial hypercholesterolemia (HoFH). HoFH is an inherited condition occurs when the body is unable to remove LDL-C from the blood causing abnormally high levels of circulating LDL-C.

Juxtapaid (lomitapide capsule) is a new medication approved for lowering cholesterol. It is approved for use only in patients with familial hypercholesterolemia already on statin mediations. Those are patients with extreme elevations in LDL cholesterol and high risk of early heart disease. It is not a statin, and is the first in a new class of medications called microsomal triglyceride transfer protein (MTP) inhibitors. Juxtapid is an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, to reduce LDL-C, total cholesterol (TC), apolipoprotein B (apo B) and non- high-density-lipoprotein cholesterol (non-HDL) in patients with homozygous familial hypercholesterolemia (HoFH).


Artificial Pancreas: FDA-Diabetic Community dialogue

artifical panc.JPG




  • FDA is helping advance the development of an artificial pancreas device system (APDS)—an innovative device that automatically monitors blood glucose and provides appropriate insulin doses in people with diabetes who use insulin
  • Forward looking Guidance issued – prior to any approved device – to encourage development
  • Recommendations on appropriate endpoints and evidentiary standards for PMA approval; pediatric development encouraged
  • Manufacturers need to also focus on Quality System: Software (including sensors) and Hardware. Software problems anticipated. Require design features to prevent malfunctioning of system.
  • Cybersecurity concerns need to be addressed.
  • Interoperability issues need to be addressed
  • Regulatory burden for new technology depends on scope
  • Encourage Pre-Submission Meeting to align on required studies and study design to meet Intended Use/Indication for Use. Identify patient population, appropriate software algorithm for dosing for designing trial
  • Medtronic has completed pivotal trial with APDS and FDA submission anticipated










ODEFSEY Clinical Pharmacology Card


ODEFSEY® (emtricitabine, rilpivirine, and tenofovir alafenamide) tablets for oral use 

Mechanism of Action ODEFSEY is a fixed dose combination of antiretroviral drugs emtricitabine (FTC), rilpivirine (RPV), and tenofovir alafenamide (TAF).
Pharmacodynamics (PD) Higher than recommended doses of RPV, 75 mg once daily and 300 mg once daily (3 times and 12 times recommended daily dose in ODEFSEY) prolonged the QTc interval.  TAF at the recommended dose and at a dose approximately 5 times the recommended dose did not affect the QT/QTc interval and did not prolong the PR interval. The effect of FTC on the QT interval is not known
Pharmacokinetics (PK) Tmax:  4 h (RPV). 3 h (FTC) and 1 h (TAF)

 Cmax (multiple dose, mcg/mL):  2.1 (FTC), NA (RPV) and 0.16 (TAF)

 AUCtau (mcg.h/mL):  11.7 (FTC), 2.2 (RPV) and 0.21 (TAF)

Ctrough (mcg/mL):  0.10 (FTC), 0.08 (RPV) and NA (TAF)

 Food Effect (high fat meal):  72% increased of AUC ( RPV). No change (FTC) and 53% increased of AUC (TAF).

 Protein Binding (% bound):  about 9 (RPV), <4 (FTC) and 80 (TAF)

 Metabolism: by CYP3A (RPV), not significantly metabolized (FTC) and by Cathepsin A, hepatocytes, and minimal CYP3A (TAF).

 Elimination: by  metabolism (RPV), by glomerular filtration and active tubular secretion (FTC) and by metabolism (TAF)

Exposure-Response Relationship Pediatric subjects 12 to less than 18 years of age, antiretroviral HIV-1-infected, had comparable PK of RPV to those in HIV-1 infected adults. There was no impact of body weight on RPV PK in pediatric subjects.

Population PK

Renal Impairment:  No clinically relevant changes in mild impirment (RPV), exposure was higher in moderate impairment and no clinically relevant changes (TAF).

 No dosage adjustment is recommended based on race or gender for FTC, RVP or TAF.

 Hepatitis B and/or C virus coinfection had no clinically relevant effect on the exposure of RPV.

Special Populations Hepatic Impairment:  Not studied (FTC), exposure was 47% higher in mild hepatic impairment and 5% higher in moderate hepatic impairment (RPV) and no clinically relevant changes (TAF).

Age did not have a clinically relevant effect on exposures of TAF up to 75 years of age. RVP and FTC have not been fully evaluated in the elderly..

Drug Interactions RPV is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV.

 Drugs that strongly affect Pgp activity (e.g., cyclosporine) may lead to changes in TAF absorption. Drugs that induce P-gp activity are expected to decrease the absorption of TAF which may lead to loss of therapeutic effect of ODEFSEY and development of resistance. Co-administration of ODEFSEY with other drugs that inhibit Pgp may result in increased absorption and plasma concentrations of TAF and possible adverse events.

 Co-administration of RPV with drugs that increase gastric pH may decrease plasma concentrations of RPV and lead to loss of virologic response and possible resistance to RPV.


ANTHIM Clinical Pharmacology Card

ANTHIM (obiltoxaximab) injection

Mechanism of Action

Obiltoxaximab is a deimmunized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that specifically binds the protective antigen (PA) of B. anthracis, thereby preventing its association with the anthrax toxin receptor on host cells.

Pharmacodynamics (PD)

Because the effectiveness of ANTHIM cannot be evaluated in humans, a comparison of ANTHIM exposures achieved in healthy human subjects to those observed in animal models of inhalational anthrax in therapeutic efficacy studies. Based on observed and simulated data, healthy subjects and humans infected with B. anthracis achieve similar obiltoxaximab median Cmax and 2-fold greater median AUCinf following a single 16 mg/kg IV dose compared to exposures associated with efficacy in rabbits and monkeys in inhalational anthrax efficacy studies.

Pharmacokinetics (PK)

The PK of obiltoxaximab are linear over the dose range of 4 mg/kg (0.25 times the lowest recommended dose) to 16 mg/kg following single IV administration in healthy subjects.

 Mean Cmax and AUCinf were 400 mcg/mL and 5170 mcg•day/mL, respectively, following a single 16 mg/kg IV dosing to healthy male and female subjects.

 Mean obiltoxaximab steady-state volume of distribution was greater than plasma volume, suggesting some tissue distribution.

 Terminal half-life is approximately 15 to 23 days in healthy 75 subjects.

Obiltoxaximab clearance was much smaller than the glomerular filtration rate indicating that there is virtually no renal clearance.

PK-PD Analysis

Not reported

Population PK

Population pharmacokinetic analysis indicated that gender (female versus male), race (non-Caucasian versus Caucasian), or age (elderly versus young) had no meaningful effects on the PK parameters for ANTHIM. 

Special Populations

ANTHIM PK have not been evaluated in children

Drug Interactions

Co-administration of 16 mg/kg ANTHIM intravenously with intravenous or oral ciprofloxacin in human subjects did not alter the PK of either ciprofloxacin or obiltoxaximab


TALTZ Clinical Pharmacology Card

TALTZ (ixekizumab) injection, for subcutaneous use 

Mechanism of Action

Ixekizumab is a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody (mAb) that selectively binds with the interleukin 17A (IL-17A) cytokine and inhibits its interaction with the IL-17 receptor. IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Ixekizumab inhibits the release of proinflammatory cytokines and chemokines.

Pharmacodynamics (PD)

No formal pharmacodynamic studies have been conducted.

Pharmacokinetics (PK)

Ixekizumab exhibited dose-proportional pharmacokinetics in subjects with plaque psoriasis over a dose range from 5 mg to 160 mg following subcutaneous administration.

 Iixekizumab bioavailability ranged from 60% to 81% following subcutaneous injection in subjects with plaque psoriasis. Administration of ixekizumab via injection in the thigh achieved a higher bioavailability relative to that achieved using other injection sites including the arm and abdomen.

 Mean systemic clearance was 0.39 L/day and the mean half-life was 13 days in subjects with plaque psoriasis.

 Mean volume of distribution at steady-state was 7.11 L  in subjects with plaque psoriasis. Clearance and volume of distribution increase as body weight increases.

PK-PD Analysis

Not reported

Population PK

Age did not significantly influence the clearance of ixekizumab in adult subjects with plaque psoriasis. 

Special Populations

No formal trial of the effect of hepatic or renal impairment on the pharmacokinetics of ixekizumab was conducted..

Drug Interactions

Drug interaction studies have not been conducted with TALTZ.

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Clinical Pharmacology Card: ZEPATIER

ZEPATIER™ (elbasvir and grazoprevir) tablets

Mechanism of Action A fixed-dose combination of elbasvir and grazoprevir which are direct-acting antiviral agents against the hepatitis C virus.
Pharmacodynamics (PD) At therapeutic concentration both elbasvir and grazoprevir do not prolong QTc to any clinically relevant extent.
Pharmacokinetics (PK) Elbasvir pharmacokinetics were similar in both healthy and HCV-infected subjects and were approximately dose-proportional over the range of 5-100 mg once daily. Grazoprevir oral exposures are approximately 2-fold greater in HCV-infected subjects as compared to healthy subjects. Grazoprevir pharmacokinetics increased in a greater than dose-proportional manner over the range of 10-800 mg once daily in HCV-infected subjects.

Elbasvir median Tmax is at 3 hours (range of 3 to 6 hours); grazoprevir median Tmax is at 2 hours (range of 30 minutes to 3 hours) in HCV-infected subjects. Steady-state Cmax for elbasvir and grazoprevir are 121 ng/mL and 165 ng/mL, respectively. Corresponding values for AUC24 are 1920 and 1420, respectively.

Elbasvir AUC0-inf and Cmax decreases by approximately 11% and 15%, respectively with high fat food in healthy subjects, whereas AUC0-inf and Cmax of grazoprevir increases by approximately 1.5-fold and 2.8-fold, respectively. These differences in elbasvir and grazoprevir exposure are not clinically relevant; therefore, ZEPATIER may be taken without regard to food.

Elbasvir and grazoprevir are extensively bound (greater than 99.9% and 98.8%, respectively) to human plasma proteins. Estimated apparent volume of distribution values of elbasvir and grazoprevir are approximately 680 L and 1250 L, respectively.

The geometric mean apparent terminal half-life for elbasvir (50 mg) and grazoprevir (100 mg) is approximately 24 and 31 hours, respectively, in HCV-infected subjects.

The primary route of elimination of elbasvir and grazoprevir is through feces with almost all (greater than 90%) of radiolabeled dose recovered in feces compared to less than 1% in urine. Elbasvir and grazoprevir are partially eliminated by oxidative metabolism, primarily by CYP3A. No circulating metabolites of either elbasvir or grazoprevir were detected in human plasma.

PK-PD Analysis Not reported.
Population PK Elbasvir and grazoprevir AUCs are estimated to be 16% and 45% higher, respectively, in subjects at least 65 years of age.

Elbasvir and grazoprevir AUCs are estimated to be 50% and 30% higher, respectively, in females compared to males.

Elbasvir and grazoprevir AUCs are estimated to be 15% and 50% higher, respectively, for Asians compared to Caucasians. Population pharmacokinetics estimates of exposure of elbasvir and grazoprevir were comparable between Caucasians and Black/African Americans.


Special Populations Exposure of elbasvir and grazoprevir in HCV-infected subjects with renal impairment with or without hemodialysis are not clinically relevant.

Relative to non-HCV-infected subjects with normal hepatic function, no clinically relevant differences in elbasvir AUC values were observed in non-HCV-infected subjects with mild, moderate, or severe hepatic impairment. Elbasvir steady-state AUC was similar in HCV-infected subjects with compensated cirrhosis compared to HCV-infected, non-cirrhotic subjects.

Relative to non-HCV-infected subjects with normal hepatic function, grazoprevir AUC values were higher by 1.7-fold, 5-fold, and 12-fold in non-HCV-infected subjects with mild, moderate, and severe hepatic impairment, respectively. Grazoprevir steady-state AUC values were higher by 1.65-fold in HCV-infected subjects with compensated cirrhosis compared to HCV infected, non-cirrhotic subjects.

Drug Interactions Elbasvir and grazoprevir are substrates of CYP3A. Co-administration of moderate and strong CYP3A inducers with ZEPATIER may decrease elbasvir and grazoprevir plasma concentrations, leading to reduced therapeutic effect of ZEPATIER. Co-administration of strong CYP3A4 inhibitors with ZEPATIER may increase elbasvir and grazoprevir plasma concentrations. 17 Grazoprevir is a substrate of OATP1B1/3. Co-administration of ZEPATIER with drugs that inhibit OATP1B1/3 transporters may result in a clinically relevant increase in grazoprevir plasma concentrations.

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BRIVIACT Clinical Pharmacology Card

 BRIVIACT® (brivaracetam) tablets, oral solution and injection

Mechanism of Action Brivaracetam has a high and selective affinity for synaptic vesicle protein 2A (SV2A) in the brain, which may contribute to the anticonvulsant effect.
Pharmacodynamics (PD) BRIVIACT did not prolong the QT interval to a clinically relevant extent.

Co-administration of BRIVIACT and ethanol caused a larger decrease from baseline in saccadic peak velocity, smooth pursuit, adaptive tracking performance, and Visual Analog Scale alertness, and a larger increase from baseline in body sway and in saccadic reaction time. The immediate word recall scores were generally lower.

Pharmacokinetics (PK) The median Tmax for tablets taken without food is 1 hour (range 0.25 to 3 hours). Effect of food is on Cmax (decreased by 37%) and Tmax (delayed by 3 hours), and not on AUC.

 Brivaracetam is weakly bound to plasma proteins (≤20%). The volume of distribution is 0.5 L/kg, a value close to that of the total body water.

 Brivaracetam metabolism involves CYP2C19. Variations in CYP2C19, production of the hydroxy metabolite is decreased 2-fold or 10-fold, while the blood level of brivaracetam is increased by 22% or 42%, respectively.

 Brivaracetam is eliminated primarily by metabolism and by excretion in the urine. More than 95% of the dose, including metabolites and is excreted in the urine within 72 hours after intake.

 The terminal half-life is approximately 9 hours.

PK-PD Analysis      Co-administration of Phenobarbital, Phenytoin or Carbamazepine  with Brivaracetam (25 mg twice daily to 100 mg twice daily) decreases plasma concentrations of Brivaracetam by 19%, 21% or 26%, respectively. Conversely, Brivaracetam increases the plasma concentrations of Phenytoin or epoxy metabolite of Carbamazepine. Interactions with carbamazepine and phenytoin can be clinically important.
Population PK There was no significant different in PK in Caucasian and non-Caucasian patients.
Special Populations Steady-state plasma clearance of brivaracetam was slightly lower (0.76 mL/min/kg) in elderly subjects (65 to 79 years old) than in young healthy controls (0.83 mL/min/kg).

 AUC of brivaracetam was increased (21%) in subjects with severe renal impairment, while the AUCs of the acid, hydroxy, and hydroxyacid metabolites were increased 3-fold, 4-fold, and 21-fold, respectively. The renal clearance of these inactive metabolites was decreased 10-fold. Hepatic Impairment

Brivaracetam exposure increased by 50%, 57%, and 59% in subjects with hepatic cirrhosis, Child-Pugh grades A, B, and C, respectively.

Drug Interactions CYP inhibitors or transporter inhibitors has no significant effect on brivaracetam exposure. Rifampin decreases brivaracetam plasma concentrations by 45%, an effect that is probably the result of CYP2C19 induction.

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ZEPATIER Clinical Pharmacology Card

ZEPATIER™ (elbasvir and grazoprevir) tablets

Mechanism of Action A fixed-dose combination of elbasvir and grazoprevir which are direct-acting antiviral agents against the hepatitis C virus
Pharmacodynamics (PD) At therapeutic concentration, both elbasvir and grazoprevir do not prolong QTc to any clinically relevant extent
Pharmacokinetics (PK) Elbasvir pharmacokinetics were similar in both healthy and HCV-infected subjects and were approximately dose-proportional over the range of 5-100 mg once daily. Grazoprevir oral exposures are approximately 2-fold greater in HCV-infected subjects as compared to healthy subjects. Grazoprevir pharmacokinetics increased in a greater than dose-proportional manner over the range of 10-800 mg once daily in HCV-infected subjects.

Elbasvir median Tmax is at 3 hours (range of 3 to 6 hours); grazoprevir median Tmax is at 2 hours (range of 30 minutes to 3 hours) in HCV-infected subjects. Steady-state Cmax for elbasvir and grazoprevir are 121 ng/mL and 165 ng/mL, respectively. Corresponding values for AUC24 are 1920 and 1420, respectively.

Elbasvir AUC0-inf and Cmax decreases by approximately 11% and 15%, respectively with high fat food in healthy subjects, whereas AUC0-inf and Cmax of grazoprevir increases by approximately 1.5-fold and 2.8-fold, respectively. These differences in elbasvir and grazoprevir exposure are not clinically relevant; therefore, ZEPATIER may be taken without regard to food.

Elbasvir and grazoprevir are extensively bound (greater than 99.9% and 98.8%, respectively) to human plasma proteins. Estimated apparent volume of distribution values of elbasvir and grazoprevir are approximately 680 L and 1250 L, respectively.

The geometric mean apparent terminal half-life for elbasvir (50 mg) and grazoprevir (100 mg) is approximately 24 and 31 hours, respectively, in HCV-infected subjects.

The primary route of elimination of elbasvir and grazoprevir is through feces with almost all (greater than 90%) of radiolabeled dose recovered in feces compared to less than 1% in urine. Elbasvir and grazoprevir are partially eliminated by oxidative metabolism, primarily by CYP3A. No circulating metabolites of either elbasvir or grazoprevir were detected in human plasma

PK-PD Analysis Not reported
Population PK Elbasvir and grazoprevir AUCs are estimated to be 16% and 45% higher, respectively, in subjects at least 65 years of age

Elbasvir and grazoprevir AUCs are estimated to be 50% and 30% higher, respectively, in females compared to males

Elbasvir and grazoprevir AUCs are estimated to be 15% and 50% higher, respectively, for Asians compared to Caucasians. Population pharmacokinetics estimates of exposure of elbasvir and grazoprevir were comparable between Caucasians and Black/African Americans

Special Populations Exposure differences of elbasvir and grazoprevir in HCV-infected subjects with renal impairment with or without hemodialysis are not clinically relevant.

Relative to non-HCV-infected subjects with normal hepatic function, no clinically relevant differences in elbasvir AUC values were observed in non-HCV-infected subjects with mild, moderate, or severe hepatic impairment. Elbasvir steady-state AUC was similar in HCV-infected subjects with compensated cirrhosis compared to HCV-infected, non-cirrhotic subjects.

Relative to non-HCV-infected subjects with normal hepatic function, grazoprevir AUC values were higher by 1.7-fold, 5-fold, and 12-fold in non-HCV-infected subjects with mild, moderate, and severe hepatic impairment, respectively. Grazoprevir steady-state AUC values were higher by 1.65-fold in HCV-infected subjects with compensated cirrhosis compared to HCVinfected, non-cirrhotic subjects.

Drug Interactions See drug interaction studies in Section 12.3 of the link below


Source :


HALAVEN Clinical Pharmacology Card

HALAVEN™ (eribulin mesylate) Injection

Mechanism of Action Exerts its effects via a tubulin-based antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage.
Pharmacodynamics (PD) Effect of HALAVEN on the QTc interval was assessed in patients with solid tumors received 1.4 mg/m2 of HALAVEN on Days 1 and 8 of a 21-day cycle. A delayed QTc prolongation was observed on Day 8, with no prolongation observed on Day 1. The maximum mean QTcF change from baseline (95% upper confidence interval) was 11.4 (19.5) ms.
Pharmacokinetics (PK) Linear PK with a mean elimination half-life of approximately 40 hours, a mean volume of distribution of 43 L/m2 to 114 L/m2 and mean clearance of 1.16 L/hr/m2 to 2.42 L/hr/m2 over the dose range of 0.25 mg/m2 to 4.0 mg/m2

 Eribulin eliminates primarily in feces as unchanged drug

 Human plasma protein binding ranged from 49% to 65%

 No accumulation observed with weekly administration

PK-PD Analysis Not evaluated
Population PK Gender, race, and age do not have a clinically meaningful effect on the PK of eribulin
Special Populations Lower starting dose of 1.1 mg/m2 is recommended for patients with moderate renal impairment
Drug Interactions No drug-drug interactions are expected with CYP system or P-gp

Source :

Debrief: Small Business Vendor Fair

Small Business Outreach Vendor fair

White Oak Campus

Feb 24, 2016




FDA and DHHS Presentations

  • Office of Info. Management (OIMT, FDA)
  • Office of Acquisitions and grants (OAGS, FDA)
    • Get DUNS#, SAM registration, NAICS Code
    • Become a subcontractor to get experience
    • FedBizzOps
  • Office of Small and Disadv. Business Utilization (OSDBU, DHHS)
    • Women owned small bizz (WOSB) encouraged
    • Core capability and FDA experience
    • Templates for Capability Statement and Business Cards

Key FDA Technology Initiative for potential contracts:

Scientific Computing.



Debrief: Medical Device Interoperability



About MDIC

Topic & Presenters

  • Introduction: Dawn Bardot, PhD, MDIC
  • FDA Draft Guidance on Interoperable Medical Devices: Bakul Patel, FDA CDRH
  • Safe Medical Device Interoperability to Enable Healthcare Transformation: Julian Goldman, MD, Massachusetts General Hospital
  • Center for Medical Interoperability Review: Ed Cantwell, Center4M


FDA Presentation


Draft guidance focuses on:

  • Design for interoperability
  • Anticipate interoperable scenarios
  • Manage and minimize risks
  • Create transparent or standards based medical device interface

FDA Slides

FDA’s position summarized in this blog

interop guidance

FDA Draft Guidance


Take the MDIC Poll to help discussions on this topic


Debrief: Human Factors & Usability Engineering

FDA Webinar Debrief

February 19, 2016



CDRH, Human Factors Team

  • Shannon Hoste, M.S., Human Factors Pre-Market Evaluation Team Member
  • Xin Feng, Ph.D., Human Factors Pre-Market Evaluation Team Member
  • Hanniebey Wiyor, Ph.D., Human Factors Pre-Market Evaluation Team Member

Presentation Overview

  • Relevant regulations and standards
  • FDA’s Human Factors guidance
  • List of highest priority devices for human factors review – draft guidance


Human Factors/Usability Engineering

Focuses on interactions between people and devices. The critical element is the device user interface, depicted as the red zone in Figure below

.user interface.JPG

FDA Human Factors Page

FDA 2016 Guidances

Clarify expectations around when to submit a HF report with a premarket submission

HFE3human factors

Summarized previously in this blog

Key Takehomes

  • Human Factors testing is a part of a robust design control subsystem
  • Submit data in premarket submissions if risk analysis indicates user error could result in serious harm
  • Consult FDA early using Q-Sub process to discuss and align on development plan and labeling implications








Drug development is a time-consuming and expensive process. There is tremendous sense of urgency for the pharmaceutical industry to develop new tools to accelerate the drug development process and to reduce attrition rate on drug candidates.

Microdosing is a tool in the early drug development. The term Phase 0 is therefore often used to refer to such studies. Dose needs to administer in microdosing study is less than 1/100 of the test substance calculated to yield a pharmacologic effect, with a maximum dose of 100 μg.

The FDA in 2006 issued a guidance document on exploratory Investigative New Drug detailing the regulatory process for microdosing clinical studies (FDA Guidance ). These studies helps to understand the bioavailability and pharmacokinetic profiles of test compounds in human, to evaluate the metabolic profiles in human or to obtain the information on the tissue distribution of test compounds in human by using molecular imaging technology.

Microdosing can be useful in the discovery of endogenous biomarkers, which would assist in the quantitative evaluation of the in vivo effects of drugs. Since the dose is sub-therapeutic level, the potential for adverse side effect to a human subject in the clinical study is considered to be minimal. The preclinical toxicology required to support microdosing is minimal. Furthermore, if human screening of compounds is done earlier in the drug development process, fewer animal studies are required before Phase I clinical trials. Therefore, animal studies can be avoided with compounds having unsuitable pharmacokinetic (PK) profiles. Hence these studies can be used as a candidate selection tool to effectively eliminate drug candidates that show sub-optimal human PK before spending time and effort in the kind of extensive toxicology that is required prior to conventional Phase 1. Ultrasensitive bioanalytical equipment and techniques are obviously required, but the substantial cost and time savings from early elimination of unviable compounds may more than justify the investment. When the drug discovery process yielded a single molecule, microdosing can still be useful in such circumstance. It can quickly establish if it is worth taking the molecule forward prior to committing large-scale resources to a full Phase I study. Sometimes a metabolic pathway is identified in human hepatocytes or liver microsomes, which is not seen in animals. Microdosing may be used to establish if the metabolic pathway occurs in vivo.

 The fundamental strengths of microdosing, improved safety, reduced cost, and time to developmental decisions, are likely to get only stronger. The concept has been widened from a purely pharmacokinetic predictive method towards addressing other questions, such as drug-drug interactions, polymorphism and looking at whether a drug is likely to reach its site of action. Microdosing study data with modelling may lead to much more reliable predictions for drug candidate selection.

There are limitations in microdosing technique. At therapeutic dose level drug may exhibit limited solubility, and absorption becomes dependent on the rate and extent of dissolution, which cannot be predicted at microdose levels since drug candidate could dissolve readily at microdose, yielding good PK. Also this study may not be able to predict nonlinear pharmacokinetic characteristics of the drug at therapeutic dose level. Microdosing study needs very sensitive analytical methods to measure circulating drug levels in blood as a function of time.


FDA Guidance

Debrief: Collaborative Approaches to Medical Device Cybersecurity

FDA Meeting Debrief

Moving Forward: Collaborative Approaches to Medical Device Cybersecurity

FDA White Oak Campus

Jan 20-21, 2016


  • FDA – CDRH
  • Chair:  Suzanne Schwartz, MD, MBA, Associate Director for Science and Strategic Partnerships


  • National Health Information Sharing Analysis Center
  • Dept. of Health and Human Services
  • Dept. of Homeland Security

Panelists: FDA, Industry, Academia, Profit & Nonprofit Cybersecurity Alliances,  National Health Information Centers, Healthcare Systems

Issue: Medical device vulnerabilities can serve as access points for entry into hospital and health care facility networks leading to compromise of data confidentiality, integrity, and availability

Objective: Engage diverse stakeholders across medical device ecosystem to discuss and identify approaches to address unresolved gaps and challenges that have hampered progress in advancing medical device cybersecurity. The attention should be on ‘total product life cycle’ – from design to obsolescence

Meeting Discussions:


Has issued 2 guidances and has evaluated information contained in premarket submissions.

  • Premarket Cybersecurity Guidance (finalized 2014) emphasizes (a) shared responsibility between stakeholders, including health care facilities, patients, providers, and manufacturers (b) addressing cybersecurity during the design and development (c) establishing cybersecurity design inputs,  vulnerability and management approach as part of software validation and risk analysis
  • Observation of Premarket submissions (2014-2015) indicated deficiencies in cybersecurity information as defined by the guidance
  • Postmarket Cybersecurity Guidance (draft issued 1/2015) emphasizes (a) collaborative approach to information sharing and risk assessment (b) manufacturer responsibilities by leveraging existing Quality System Regulation (c) alignment with Presidential Executive Orders and NIST Framework (d) Incentivizing the “right” behavior (e) using risk-based approach to addressing public health risks

Panel and Breakout Sessions

Panel experience and best practice sharing across several topics

Cyber threat landscape, implementation of NIST, Information Sharing and Analysis Organization (ISAO), Postmarket vulnerability handling and disclosure, manufacturing challenges, addressing gaps and challenges to strengthening cybersecurity, current activities in healthcare and public health sector, risk assessment tools, adapting and implementing medical device cybersecurity

Breakout sessions involving 400 attendees to share opinions and proposals for ISAOs, Coordinated vulnerability disclosure, gaps and action plan

Key Takehomes:

  • Cybersecurity is critical for total product lifecycle and is a collaborative effort across multiple stakeholders. Recognition of hackers ‘from hoodies to business suits’
  • There should be information sharing (profit/nonprofit organization) and collaborative discussion of setting of cybersecurity standards, conformity assessments and certifications across all stakeholders to strengthen the ecosystem; consideration of centralized listing
  • Experience from other sectors (eg banking, homeland security) can be leveraged; however, medical device approach needs to be grounded in context of patient safety and effectiveness
  • Device manufacturers should follow the principles of Premarket Cybersecurity Guidance

ACTION : All stakeholders to review and comment on the draft Postmarket Cybersecurity Guidance by April 21, 2016

 Graphic Memorialization:

By Stephanie Brown @stephscribes



postmarket  Premarket






Premarket Cybersecurity Guidance

Postmarket Cybersecurity Guidance

Cybersecurity Page







NINLARO® (ixazomib) Capsule for Patients with Multiple Myeloma

A reversible proteasome inhibitor, preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome.

Pharmacodynamics (PD) Did not prolong the QTc interval at clinically relevant exposures
Pharmacokinetics (PK) Approximately 58% absolute bioavailability (median Tmax of 1 hour) in patients.

A 28% and 69% decreased in ixazomib AUC and Cmax, respectively, following the administration of NINLARO with a high-fat meal

AUC increased in a dose proportional manner over a dose range of 0.2 to 10.6 mg (i.e., 0.05 to 2.65 times the approved recommended dosage)

Accumulation approximately 2-fold

Systemic clearance was approximately 1.9 L/h and terminal half-life (t1/2) was 9.5 days

Extensive metabolism with both non-CYP and CYP enzymes contributing to ixazomib metabolism. At higher than clinical concentrations (in vitro), CYP3A4 is predominant (42%)

Plasma protein binding was approximately 99%.

Approximately 62% of the administered radioactivity was excreted in the urine (< 3.5% as unchanged drug) and 22% in the feces

PK-PD Analysis Did not prolong the QTc interval at clinically relevant exposures based on pharmacokinetic-pharmacodynamic analysis of data from 245 patients
Population PK There was no clinically meaningful effect of age (range 23-91 years), sex, body surface area (range 1.2-2.7 m2), or race on the clearance of ixazomib
Special Populations PK of ixazomib was similar in patients with normal hepatic function and in patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1-1.5 x ULN and any AST)


PK of ixazomib was similar in patients with normal renal function and in patients with mild or moderate renal impairment (creatinine clearance ≥ 30 mL/min). Mean AUC was 39% higher in patients with severe renal impairment or ESRD requiring dialysis as compared to patients with normal renal function.

Drug Interactions Co-administration of ixazomib with rifampin decreased ixazomib Cmax by 54% and AUC by 74%


Co-administration of ixazomib with clarithromycin did not result in a clinically meaningful change in the systemic exposure of ixazomib


Ixazomib is a low affinity substrate of P-gp, but is not expected to cause transporter-mediated drug-drug interactions.

Source :


NUCALA Clinical Pharmacology Card


NUCALA® (Mepolizumab) for subcutaneous (SC) injection for Severe Asthma Aged 12 Years and Older


Mechanism of Action Interleukin-5 (IL-5) antagonist monoclonal antibody (IgG1 kappa), responsible for the growth and differentiation, recruitment, activation, and survival of eosinophils
Pharmacodynamics (PD) Blood eosinophils decreased in a dose-dependent manner for doses 12.5 mg SC, 125 mg SC, 250 mg SC
Pharmacokinetics (PK) Exhibited approximately dose-proportional pharmacokinetics over a dose range of 12.5 to 250 mg. in subjects with asthma

 Accumulation approximately 2-fold at steady state

 Approximately 80% is absorbed following SC administration in the arm

 Central volume of distribution of mepolizumab in patients with asthma is estimated to be 3.6 L for a 70-kg individual

 Mean terminal half-life ranged from 16 to 22 days

Proteolytic enzymatic degradation that is widely distributed in the body

PK-PD Analysis Have not been reported
Population PK There was no significant effect of race and gender on mepolizumab clearance

There was no significant effect of age on mepolizumab clearance, ranging in age from 12 to 82 years

Special Populations No clinical trials have been conducted to investigate the effect of renal impairment or hepatic impairment on the pharmacokinetics of mepolizumab
Drug Interactions No formal drug interaction studies have been conducted

Source :



Mechanism of Action

Fixed-dose combination of antiretroviral drugs elvitegravir (EVG), boosted by the CYP3A inhibitor cobicistat (COBI), emtricitabine (FTC), and tenofovir alafenamide(TAF)

Pharmacodynamics (PD)

Effect on QT interval is not known

Pharmacokinetics (PK)

Median Tmax: EVG: 4 hours; COBI: 3 hours; FTC: 3 hours; TAF: 1 hour

Food Effect: EVG AUC was increased by 34% and 87% when GENVOYA was co-administered with a light meal and high fat meal, respectively. No clinically meaningful food effect on COBI, FTC or TAF was observed.

Median Terminal half-lives: EVG: 12.9 hours; COBI: 3.5 hours ; FTC: 10 hours; TAF: 0.51 hours

Metabolism: EVG: CYP3A (major) and UGT1A1/3 (minor): COBI: CYP3A (major) and CYP2D6 (minor): FTC: Not significantly metabolized; TAF: Cathepsin A (major), carboxylesterase 1 (minor), and CYP3A (minimal)

Excretion: FTC is excreted renally; TFV (the primary metabolite of TAF) is excreted renally; EVG and COBI metabolites are primarily eliminated in feces

Plasma protein binding: EVG: ~99%;  COBI: ~98% ; FTC: <4%; TAF: ~80%

PK-PD Analysis

No exposure-response relationships for safety or efficacy were identified for any of the components of GENVOYA at the approved recommended dosage.

Population PK

No dosage adjustment is recommended based on race or gender

Special Populations

No dosage adjustment is recommended based on creatinine clearance ≥30 mL/min, mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, or age ≥12 to ≤75 years.

Renal Impairment: GENVOYA is not recommended in patients with estimated creatinine clearance below 30 mL/min.

Hepatic Impairment: GENVOYA is not recommended in patients with severe hepatic impairment (Child-Pugh Class C).

Drug Interactions

GENVOYA can alter the concentration of drugs metabolized by CYP3A or CYP2D6.

Coadministration of GENVOYA is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events, and drugs that may lead to reduced efficacy of GENVOYA and possible resistance, such as potent CYP450 inducers.

Coadministration of GENVOYA is not recommended with rifabutin, rifapentine, salmeterol, and/or colchicine in patients in patients with renal or hepatic impairment.

Consider alternatives to the coadministration of GENVOYA with oxcarbazepine, systemic dexamethasone, and/or inhaled/nasal fluticasone.

Consider alternatives to the coadministration of GENVOYA with contraceptive patch, vaginal ring, injectable contraceptives, and oral contraceptives containing progestogens other than norgestimate.

Dose reduction may be necessary for sedative/hypnotics, neuroleptics, midazolam, and beta blockers when coadministered with GENVOYA.

Specific dosage regimens are required for phosphodiesterase-5 inhibitors, colchicine, and bosentan when coadministered with GENVOYA.

Initiate with the lowest starting dose of atorvastatin when coadministered with GENVOYA and titrate carefully while monitoring for safety.

Separate GENVOYA and antacid administration by at least 2 hours.

The maximum daily dosage of ketoconazole or itraconazole should not exceed 200 mg per day when coadministered with GENVOYA. Assessment of benefit/risk is recommended to justify use with voriconazole.



Nanoparticles in Drug Development


Nanoparticle technologies have revolutionized the drug development process and change the landscape of the drug industry. Nanoparticles (NP) could improve the aqueous solubility, dissolution rate, and absorption of poorly water-soluble substances.

Addressing Pharmaceutical Unmet Need : Major issues associated with poorly water-soluble compounds are poor bioavailability, fed/fasted variation in bioavailability, lack of dose-response proportionality and that leads to suboptimal dosing, need a pharmacokinetic (PK) booster to enhance bioavailability, and noncompliance by the patient, i.e., inconvenience dosing schedules.

Characteristics: NP can be defined as solid particles with a size in the range of 10-1000nm. The increased surface area of NP will enhance the dissolution of poorly water soluble drug substances. The chance gravitational settling is less for NP  because of their small size and can be suspended easily in liquid formulation. The NP approach is suitable for highly potent compounds (low dose) but it is not practical when the dose requirement may be big. In recent years nanotechnology is gaining popularity by formulators for reformulating the old formulation of poorly soluble compounds. For marketed products requiring lifecycle extension opportunities, NP formulation strategies provide a means to develop a new drug-delivery platform with improved therapeutic outcome incorporating the existing drug, thus creating new avenues for addressing unmet medical needs.

Pharmaceutical Application : An increasing number of the drug candidates synthesized each year by pharmaceutical companies which may have poor water solubility and many of these promising compounds are rejected from development because traditional formulation approaches will not be able to improve bioavailability. Nanotechnology could rescue these compounds. For new chemical entities development, the nanotechnology can be of great value in preclinical pharmacokinetics and efficacy/ safety assessment studies in the early development phase. Drug formulation with NP could reduce or eliminate food-effect related variability resulting in no dosing restriction since NP improve the solubility of drug substances. There are several techniques to make drug NP out in the literature, e.g bottom-up (Precipitation methods), top-down etc.

Disposition : Enhancing solubility and dissolution rate of poorly soluble compounds correlates with improved PK profile since dissolution kinetics is the primary driving force behind the improved PK/ bioavailability of NP formulations of poorly water soluble compounds. The enhanced bioavailability should be translated to faster onset of action that may translate into improved therapeutic outcome.

Marketed products: Oral products developed using nanoparticle technology are in the market and listed below: Rapamune (Sirolimus); Emend (Aprepitant), TriCor (Fenofibrate), MegaceES (Megestrol). Avinaza (Morphine sulphate),  Focalin (Dexmethyl-phenidate HCl),  and Zanaflex (Trizanidine HCl) and the intravenous products: intravenous nutritional fat emulsion (Intralipid) and liposomal products (Doxil, AmBisome).

Clinical Pharmacology Card


ALECENSA® (alectinib) capsule

Mechanism of Action Tyrosine kinase inhibitor targeting anaplastic lymphoma kinase & rearranged during transfection
Dosage 600 mg twice daily
Pharmacodynamics (PD) QT interval prologation assessed at 600 243 mg twice daily
Pharmacokinetics (PK) Major active metabolite M4 by CYP3A4

Dose-proportional increases over the dose range of 460 mg to 900 mg (daily

Mean accumulation ~6-fold for both at steady-state

Tmax  4 hour

T1/2  33 hr (alectinib), 31 hr ( M4)

Absolute bioavailability 37%

High-fat, high-calorie meal increased the combined exposure by 3.1-fold

Plasma protein binding 99% for both

Excretion in feces 84% as alectinib, 6% as M4.

PK-PD Analysis Have not been reported
Population PK Have not been reported.



Special Populations No dose adjustment mild and moderate renal impairment, mild hepatic impairment.

Age, body weight, mild hepatic impairment, mild to moderate renal impairment,  race, and sex no clinically meaningful effect on systemic exposures of alectinib and M4.

Drug Interactions Strong CYP3A inhibitor or a strong CYP3A inducer or an acid-reducing agent (esomeprazole) no clinically meaningful effect


Physiologically based Pharmacokinetic Modeling approach in Pediatric Drug Development



Pharmacokinetic (PK) parameters for pediatric patients have traditionally been scaled using a linear per kilogram model.  This paradigm has resulted in under- and overdosing, depending on the specific age group.

Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models can bridge pediatric and adult pharmacology. Assuming that the PD is similar in pediatrics and adults, creating a comparable PK profile requires a more logical approach based on the development of pediatric PBPK models.

The general concept of PBPK modeling is to mathematically describe relevant physiological, physicochemical, and biochemical processes that determine the pharmacokinetics of a compound in as much detail as is appropriate or needed. PBPK models map the complex mechanistic drug movements in the body to a physiologically realistic structure. It needs to incorporate information about developmental physiology and ontogeny of cytochrome P450 and their use to extrapolate drug pharmacokinetics from adults to children and to explore age-related changes.

In recent years, the implementation of PBPK models in pediatric drug development has become more attractive, encouraged by an increased awareness of interest in pediatric research, especially after the new regulations on medicinal products for pediatrics. However, lack of good in vitro and in vivo data could cause PBPK model to under or over predict the pediatric PK.

PK studies in children have limitation of sampling times; therefore appropriate methods such as the population PK (PPK) approach, are necessary for analysis of the PK data. PPK allows the estimation of population and individual parameters as well as intra- and intersubject variability and also the effects of predefined covariates. The PPK approach has a number of attractions for studying PKPD in children: it is less invasive and can thus be considered as more ethical in this age group, and PK sampling times are flexible and can be taken without causing the inconvenience to the patient. However, the choice of the PK sampling design has an important impact on the precision of population parameter estimates.

Several commercial software packages are available in developing PBPK models. Simcyp software (, allows simulation of complex absorption, distribution, metabolism, and excretion outcomes involving multiple drug interactions and parent drug and metabolite profiles. Software also allows the simulation of virtual patient populations such as obese/morbidly obese individuals and patients with renal impairment or liver cirrhosis, and include a clearance prediction model that incorporates knowledge about growth, maturation of various organs and tissues involved in drug metabolism and elimination across pediatric age groups to predict clearance in children using adult values.






Clinical Pharmacology Card

TAGRISSO® (osimertinib)


Mechanism of Action Kinase inhibitor of the epidermal growth factor receptor (EGFR)
Pharmacodynamics (PD) QTc interval prolongation potential :  Maximum mean change from baseline = 16.2
Pharmacokinetics (PK) Dose-proportional increases in systemic exposure : 20 – 240 mg dose(i.e., 0.25 to 3 times the approved recommended dosage).

 Accumulation 3-fold following qd dosing.

 Plasma protein binding likely to be high based on  physiochemical properties

 Mean Terminal half-life  48 hours

 Primarily metabolized by CYP3A.          

Excretion : 68%  (feces), 14% (urine), 2% (unchanged)

High-fat, high-calorie meal enhanced the Cmax and AUC of osimertinib by 14% and 19% resp. vs. fasting

PK-PD Analysis Concentration-dependent QTc interval prolongation of 14 msec at 80 mg dose
Population PK No dose adjustment is recommended in patients with mild or moderate renal impairment  and mild hepatic impairment.
Special Populations No clinically significant differences in the PK based on age, sex, ethnicity, body weight, smoking status, mild or moderate renal impairment, or mild hepatic impairment

Effect of severe renal impairment, hemodialysis, or moderate to severe hepatic impairment on exposure unknown

Drug Interactions Avoid concomitant administration with strong CYP3A inhibitors or inducer





Model based pediatric dose selection



Current  Approaches and Challenges 

Pediatric clinical trials are becoming more prevalent and are now typically mandatory within clinical development plans. The important challenge in pediatric studies is in selecting a safe and effective dose or dose range.

System Pharmacology and Pharmacometrics  (PK) provide for development of model-based approaches to describe and understand important age-related factors influencing drug disposition and response in pediatric patients.

The application of Modeling and Simulation provide for better estimates of pediatric doses.

The Extrapolation of Efficacy findings from adults to the pediatric population has streamlined the development process especially for studies in older children.

According to the literature, the weight-corrected doses for drugs eliminated by renal excretion or metabolism involving CYP2C19, CYP2D6, N-acetyltransferase 2, or uridine diphosphate glucuronosyltransferases are similar in children and adults.

Unmet Need:  Focus on developmental changes in infants as well as further developing a paradigm for conducting PK/efficacy studies in infants, and children remain important unmet needs. PK of drugs in children may differ from adults for several reasons: variability due to age, gender, body composition, functionality of liver and kidneys and maturation of enzymatic systems throughout the life span from neonates to adults are all potential sources of pharmacokinetic differences.

There are other challenges that arise during pediatric clinical trials which may not be apparent during clinical trials in adults such as recruitment difficulties, lower limits on blood collection volumes, the lack of surrogate markers which predict clinical outcome and the difficulty of dose selection in a rapidly changing population.

Additional Considerations

Children’s growth can be investigated using readily observable demographic factors such as weight and age.

Size is the primary covariate and can be referenced to a 70-kg person with allometry using a scale to the ¾ power coefficient for clearance and 1 for volume. The use of these coefficients is supported by fractal geometric concepts and observations from diverse areas in biology. Lean body mass might be expected to do better than total body weight when there are wide variations in fat affecting body composition.

Sigmoid Emax model best describes the gradual maturation of clearance in early life leading to a mature adult clearance. Assuming similar exposure–response relationships between adult and children, efficacy in children is warranted if the same exposure can be achieved in either population.

Case Studies

  1. Small molecule (desloratadine; Gupta et al. Br J Clin Pharmacol, 64, 174-184, 2007
  2. Large molecule (peginterferon alfa-2b; Xu, Gupta, et al. Eur J Clin Pharmacol, 69, 2045-2054, 2013

Desloratadine Dose Selection:

We combined data from the pediatric study with adult data for population pharmacokinetic analysis to determine doses of desloratadine suitable for administration to children aged ≥ 6 months-≤ 2 years in clinical and efficacy studies.

Single doses of 0.625 mg (1.25 ml) and 1.25 mg (2.5 ml) desloratadinesyrup were well tolerated in this age group. Because the study was designed to collect only a minimal number of blood samples, a population pharmacokinetic modelling approach was used.

Results of the pharmacokinetic analysis indicate :

  • desloratadine apparent clearance rates were slower in the pediatric group studied than in adults, and that the 0.625 mg dose appeared to be suboptimal for both children aged ≥ 6 months-<1 year and for those aged ≥ 1 year- ≤ 2 years, particularly with respect to Cmax.
  • Variability between subjects in the model parameters was moderate, but was consistent with estimates of pharmacokinetic variables obtained with noncompartmental analysis. No systematic bias was observed in parameter estimation.
  • On the basis of the results of this analysis, to ensure similar desloratadine exposure to that seen in adults, the age appropriate doses for children aged ≥ 6 months-<1 year and for those aged ≥ 1 year- ≤2 years were established as 1.0 mg and 1.25 mg, respectively.
  • Desloratadine is extensively metabolized in the liver to its active metabolite, 3-OH-desloratadine. It is known that some individuals, termed poor metabolizers, have a reduced ability to form the active metabolite. Exposure to desloratadine has previously been shown to be approximately six-fold greater in poor metabolizers than in the rest of the population, with a similar magnitude of reduction in the formation of 3-OH-desloratadine in adults and children given age-appropriate doses. Based on the observed AUC ratio of 3-OH-desloratadine relative to desloratadine, the proportion of poor metabolizers in this study population was approximately 7%. The poor metabolizers are African American. This is consistent with the findings of a large clinical study in older children and adults, which found an age-independent prevalence of this phenotype of 6%.
  • Despite the difference in exposure to desloratadine in poor metabolizers, data from studies in patients as young as 2 years have shown it to be well tolerated. This was also the case in this study, with no differences in the safety profile of desloratadine between poor metabolizers and other subjects. These pediatric dose concentrations yielded systemic desloratadine exposures similar to those seen in adults.

Peginterferon alfa-2b dose selection:

The final population pharmacokinetic model of PEG-IFN alfa-2b was a one-compartment model with first-order absorption, first-order elimination, exponential inter-individual variability on apparent clearance, and with a combination additive and proportional residual error model. The body surface area normalized apparent clearance of PEG-IFN alfa-2b was similar across all age groups (3-17 years) and the mean estimated CL/F at age 19 was 1.38 L/hr, which is similar to the CL/F in adults of 1.29 L/hr to 1.54 L/hr. Populations in pediatric studies frequently cover a much wider relative range in body size than comparable studies in adults; the current pediatric data set confirms that size parameters—including body weight, height, BMI, and body surface area are highly correlated with other developmental or maturation-related parameters. Previous clinical trials have shown PEG-IFN alfa plus ribavirin to be an effective treatment option in children and adolescents. These studies have revealed that many of the predictors of sustained viral response (SVR) in adults are also applicable when treating children. Rates of SVR are lower among children with genotype 1 infection compared to genotype 2 or 3 (53% vs 93%, P = .0005), and within the genotype 1 population, baseline viral load <600,000 IU/mL is associated with increased rates of SVR compared to high baseline viral load. (72% vs 29%, P = 0.0006). Furthermore, rapid- and early virologic response are also strong predictors of SVR in the pediatric population with positive predictive values of 89% and 84%, respectively.

As with all studies of this type, several factors may limit interpretation of the data. The concentrations from sparse pharmacokinetic sampling may not contain enough information to estimate Ka accurately for each individual, and the estimated standard error of inter-individual variability for Ka was greater than for CL/F and V/F. In addition, there were 5 outliers with low CL/F whose observed concentration of PEG-IFN alfa-2b tended to increase after week 8, leading to lower CL/F values compared with other patients. To assess this further, an additional population pharmacokinetic analysis was performed, which included week 1-8 concentration data for all 107 patients. The final population pharmacokinetic one-compartment model suggests age-dependent increases in clearance and volume of distribution of PEG-IFN alfa-2b in pediatric patients with chronic hepatitis C. The body surface area normalized apparent clearance was similar across pediatric age groups, validating the use of a body size–adjusted dosing schedule in pediatric subjects.




Juvenile rheumatoid arthritis treatment with model based dosing information



Arthritis causes inflammation of the joints that leads to pain, stiffness and swelling. When arthritis occurs in children younger than age 17, it is called juvenile arthritis.

Some children may experience symptoms for only a few months, while others have symptoms for the rest of their lives. About 300,000 children in the United States have some form of the disease.

Juvenile rheumatoid arthritis (JRA), also called juvenile idiopathic arthritis (JIA). JRA is thought to be an autoimmune disease, the body’s immune system attacks some of its own tissue and cells the same way it would react against a foreign invader such as a virus or bacteria. Certain gene mutations may make a person more susceptible to environmental factors, such as viruses that may trigger the disease.

In JRA, the lining of the joint (called synovial membrane) becomes inflamed and enlarged, limiting movement and causing pain and tenderness. Key symptoms include a rash on the cheeks, sensitivity to sunlight, mouth or nose sores, joint pain, seizures or other signs of neurological problems, and chest pain. Inflamed membranes release enzymes those cause further damage to the bone and cartilage. This type of joint and bone damage may cause problems in a growing kid If the growth areas of the bones are affected, the bones may grow at different rates so that one bone may develop abnormally in shape or size. The result could be, for example, that one leg might be permanently shorter than the other.

There are several subcategories of juvenile rheumatoid arthritis: Systemic onset type (begins with a whole-body), Pauciarticular onset disease (fewer than five joints are affected), Polyarticular disease (five or more joints are affected, usually involves the small joints), Juvenile axial spondylo arthritis (effects involves the large joints of the lower back and hips), Reactive arthritis (exposure from bacteria, in particular shigella or salmonella), Juvenile psoriatic arthritis (have psoriasis, and have a genetic component), and Juvenile systemic lupus erythematosus (cause inflammation and tissue damage in many areas of the body).

MEDICATIONS: (click on underlined for more information)

First lines of medications for an acute stage of the disease are nonsteroidal anti-inflammatory drugs (NSAIDs) to provide relief the inflamed joints. They work by decreasing the amount of an enzyme found in inflamed joints. The same enzyme, however, helps to protect the stomach, so NSAIDs often cause stomach irritation and ulcers. Low doses of NSAIDs are available over-the-counter, including ibuprofen and naproxen. COX-2 inhibitor is a prescription drug that is thought to be safer for the stomach because it does not have as much of an effect on the enzyme that protects the stomach. Children with severe juvenile arthritis have been treated with drugs that suppress the body’s immune response such as corticosteroids and methotrexate. Corticosteroids can have serious side effects, including weight gain, weakened bones, and interference with growth. Other medications may be effective, including hydroxychloroquine, sulfasalazine, leflunomide, azathioprine and cyclosporine. Thalidomide may be effective for certain children with JRA, but care must be taken to avoid pregnancy. Both polyarticular and systemic JIA are treated with biologics.

Biologics target cytokines (control/drive inflammation) such as tumor necrosis factor (TNF), interleukins (IL), and other naturally occurring proteins involved in stimulating the body’s immune response. These are used in the treatment of JIA, generally given intravenously or subcutaneously, includes adalimumab (Humira), etanercept (Enbrel) and tocilizumab (Actemra), Infliximab (Remicade), abatacept (Orencia), anakinra (Kineret), canakinumab (Ilaris) and rituximab (Rituxan). Different biologics tend to work better for different subgroups of the disease.


M&S approach provided appropriate dosing recommendation with the risks and benefits assessments:

  • Exposure-response modeling of canakinumab in the avoidance of flares in children with systemic juvenile idiopathic arthritis Y Xiong  et al., Pediatr Rheumatol. 2013; 11(Suppl 2), 181.
  • Anakinra pharmacokinetics in children and adolescents with systemic-onset juvenile idiopathic arthritis and autoinflammatory syndromes. Saik Urien et al, BMC Pharmacology and Toxicology 2013, 14:40

Quantitative Systems Pharmacology (QSP)


Use of Quantitative Systems Pharmacology in Pharmaceutical R&D

What :

Quantitative systems pharmacology (QSP) modeling and simulation is integration of two disciplines that have been increasingly useful in pharmaceutical R&D; combination of Systems Biology and Quantitative Pharmacology.

  • Systems Biology is the field of biomedical research including those between genes and biologically active molecules to develop models of these systems that are usually qualitative in nature.
  • Quantitative Pharmacology is the field of biomedical research that seeks to use computer aided modeling and simulation to increase our understanding of the pharmacokinetics  and pharmacodynamics of drugs, and to aid in the design of preclinical and clinical experiments.
  • QSP is a rapidly growing discipline that incorporates computational modeling and experimental methods to investigate drug action.

Traditional pharmacokinetics (PK) has been a major challenge in classical drug discovery: many compounds failed because they had unfavorable PK half-lives or distribution in humans. The traditional PK rarely takes into account the physiology and biology of the human body. However, physiologically based PK (PBPK) is built mainly from drug-independent system information. This has been attributed to a greater connectivity to in vitroin vivo extrapolation (IVIVE) techniques for predicting drug absorption, distribution, metabolism, and excretion (ADME) and their variability in humans. PBPK–IVIVE linked models have repeatedly shown their value in guiding decisions when predicting the effects of intrinsic and extrinsic factors on PK of drugs. Therefore, it will be a better strategy in extending the success of PBPK–IVIVE to pharmacodynamics and drug safety.


QSP combines both computational and experimental methods to validate and apply new pharmacological concepts to the development and use of small molecule and biologic drugs. QPS would maximize therapeutic benefit and minimize toxicity and implement a precision medicine.  QSP models will be critical to increasing the probability of success will be in the target identification stage, the transition from pre-clinical to first in man studies, the transition from healthy volunteer to patient studies, and the transition from adult to pediatric. Modeling and simulation to guide the design of experiments intended to test hypotheses. In addition to the utility in translation between experimental models, QSP allows prediction of the effects of multiple therapeutic interventions in combination. QSP can provide the frame work in which to evaluate the potential combination medications prior to testing in the clinic, by providing a fundamental systems and quantitative understanding of how these different mechanisms will interact. Reported work in the literature described the use of QSP modeling and simulation to facilitate biomedical research and pharmaceutical R&D. Most of these publications have been focused on PK, since the processes that govern drug absorption, distribution, metabolism, and excretion are better established compared to those that govern disease biology and PD. In a report author demonstrated that the use of the physiologically based PK (PBPK) models for prediction of PK in children prior to the conduct of the first pediatric clinical study.. There are software packages available that can be used to develop and run models and it will allow prediction of in vivo drug PK based on the in vitro properties of the molecule.  QSP models that predict both PK and PD are much more complex, and tend to be disease area specific. In an another published work, the QSP model of cognitive deficit in schizophrenia and was able to simulate the enhancement of cognition with clozapine and risperidone, as well as the worsening of cognition with gama-aminobutyric acid modulators lorazepam and flumazenil. Published work can be found in scientific journals like:

CPT: Pharmacometrics & Systems Pharmacology



Disease Progression Model in Drug Development


Disease progression describes the change of disease status over time as function of disease process and treatment effects. In practice, biomarkers are frequently used as a proxy to monitor disease status. Chronic diseases usually progress slowly over time. For example, Chronic Obstructive Pulmonary Disease  can take well over 10 years to evolve from Stage I (mild) to Stage IV (very severe). It may also take 10 years for Congestive Heart Failure to progress from Stage I (mild) to Stage IV (severe). Late detection and intervention for such chronic diseases significantly increases the burden on both the patients and the healthcare system. Being able to detect the development of chronic diseases at an early stage is instrumental to preventive care and personalized medicine.

A better understanding of disease progression is beneficial for early diagnosis and appropriate individual therapy. There are many different approaches for statistical modelling of disease progression proposed in the literature, including simple path (Linear Progress) models up to complex model. In disease progression modeling (DPM), the progression in time of a disease in an individual is represented as a mathematical function. Initially, a model is produced that characterizes a given disease’s time profile in the absence of therapeutic intervention; this is a base model. Changes due to active treatment are superimposed onto the base model to simulate the effect on the disease of a drug. As the base model is not dependent on any treatment, it may be modified for use in simulating for other treatments. Disease progression models offer greater insight into data obtained from clinical trials, allowing for better study designs. DPM of the progression of a target disease with computational methods is an important technique that can help with the early detection and management of chronic diseases. By characterizing the entire disease progression trajectory, DPM also facilitates disease prognosis improvement, drug development, and clinical trial design.

Linear Progress Model: The linear model assumes constant rate of change of clinical effect or biomarker that reflects the disease status (D) at any time (T) from initial observation from the patient. The rate of change can be defined in terms of baseline disease status (D0) with a slope factor (s), reflects the change from baseline with time:

D(T) = D(0) + s*T

The linear model was further modified by the addition of an effect compartment (Ece) in order to allow for a delay between the initiation of treatment and the time to observable response:

D(T) = D(0) +(Ece(T) + s) *T

In this model, the disease status would not return to the pretreatment course when therapy was discontinued, but would be expected to result in a permanent improvement. Linear equations have been used to describe the progression of several diseases, including Alzheimer’s disease and schizophrenia. In these models, the disease progression component included a placebo response model, incorporating both the trajectory of disease as well as a transient change in disease status attributed to placebo response. DPM is an additional evaluation tool that has an improved ability to detect a drug effect and provides useful dosing information for prescribers. Modeling is also an important component in the regulatory requirements for a new drug application. Models of disease progression have been used for a wide variety of clinical indications. The use of the population approach for studies of disease progression refers to describing the natural history of disease reflected in repeated measures of disease status. Disease status is a general term that refers to any quantifiable variable describing disease at a particular point in time. Observations of disease status, like those of drug concentration or drug effect, can often be made repeatedly in the same patient.

Disease progress models incorporate both pharmacokinetics and pharmacodynamics to describe drug action. Natural history progression models incorporate the clinical and pathophysiological features of disease. By combining them, a more complete picture can be created of the roles of disease and treatments in understanding clinical pharmacology and improving patient care. The use of models to describe the disease progress is good tool that allows the modelers to assess the effect of drug treatment on the time course of disease. The mechanism of action of the drug may suggest innovative combination therapies or novel treatment approaches that would not have been considered without knowledge of the disease and the effect of drug on disease progress. In the literature there are many suggestions of DPM. Each has certain assumptions and models disease progression in a different way.

Model-Based Drug Development (MBDD)



mbddModel-based drug development (MBDD) is an approach that is used to organize the vast and complex data streams that feed the drug development pipelines of small molecule and biotechnology sponsors. MBDD relies on the construction of quantitative relationships to connect data from discrete experiments conducted along the drug development pathway. These relationships are then used to ask questions relevant at critical development stages, hopefully, with the understanding that the various scenarios explored represent a path to optimal decision making. The FDA critical path document characterizes MBDD as the development and application of pharmaco-statistical models of drug efficacy and safety from preclinical and clinical data to improve both drug development knowledge management and decision-making. Such data streams are ultimately reviewed by the global regulatory community as evidence of a drug’s potential to treat and/or harm patients. As MBDD becomes more integrated into the pharmaceutical research community, a more rational explanation for decisions regarding the development of new agents as well as the proposed treatment regimens that incorporate both new and existing agents can be expected. By providing quantitative justification for trial design, dose selection and decisions during trial execution, MBDD can improve the efficiency of clinical dev elopment. Quantitative clinical pharmacology can also boost the quality of a drug’s regulatory package. The concept of a MBDD paradigm is to construct quantitative expressions about target–drug activity drug-–exposure → exposure–(biomarker) response (efficacy/adverse events) → response–(clinical) outcome relationships, so that these questions promote assumption and scenario testing prior to clinical investigation.

Some examples of the application of MBDD at different stages of drug development include:

Drug Candidate Selection:

Drug discovery and development involve the utilization of in vitro and in vivo experimental models. Different models, ranging from test tube experiments to cell cultures, animals, healthy human subjects, and even small numbers of patients that are involved in clinical trials, are used at different stages of drug discovery and development for determination of efficacy and safety. The proper selection and applications of correct models, as well as appropriate data interpretation, are critically important in decision making and successful advancement of drug candidates.

Simcyp’s (Simulators) R&D activities focus on the development of algorithms along with population and drug databases for modelling and simulation (M&S) of the absorption and disposition of drugs in patients and specific subgroups of patients across different age/sex ranges. Simcyp’s allow predicting the drug absorption, distribution, metabolism and excretion and potential drug-drug interactions. The Simcyp models use experimental data generated routinely during pre-clinical drug discovery and development from in vitro enzyme and cellular systems, as well as any relevant physico-chemical attributes of the drug and dosage forms. A model-based approach can utilize available in vitro and/or in vivo data to predict the pharmacokinetic profile of a drug in humans prior to the first human exposure. These early predictions can be a key component in the rationale for selecting the first dose to administer to humans. Specifically, doses can be selected which are predicted to provide an acceptable safety margin relative to exposures achieved in non-clinical toxicology studies.

Phase 1 Clinical Development:

Early human PK or PD data can be used to develop the next stage of models of human exposure and/or PD response. A real-time model-based approach may be particularly useful to guide dose escalation during the conduct of ascending-dose studies. Upon completion of these studies, simulations based on the final model(s) can be a valuable resource when designing and optimizing longer-term studies.

Phase 2 Proof of Concept:

Data collected at the proof of concept stage can be used to develop ever more robust models. At this stage of development model-based predictions can be critical to selection of study designs, optimal doses, and dosing regimens to progress into Phase 3.

 Phase 3 Clinical Development:

At this stage in development PK and PD (biomarkers) data are typically collected in a broad sample of the target population. These data allow further development of PK and PD models in preparation for regulatory filing and marketing. A key aspect of this stage of MBDD is characterizing the variability in drug concentrations and drug response. Identification of clinically relevant demographic factors (e.g., age, body weight, renal  and hepatic functions) that impact variability is often a critical step in development of these models. Information gleaned from these models often serves as a foundation for developing dosing guidance in special populations (renal/hepatic impairment), age groups (elderly/children) or based on other clinically relevant factors identified in the model.

MBDD is a tool that is increasingly used throughout the drug discovery and development continuum to support fast and rationale decision making and has thereby the potential to accelerate and increase the cost-effectiveness of the drug development process.  The use of suitable biomarkers (PD markers) in MBDD, has shown its merits in therapeutic areas, especially in early clinical development.

Treatments for Crohn’s Disease

crohnsCrohn‘s disease is a chronic inflammatory condition that causes inflammation, or swelling, and irritation of any part of the digestive tract— also called the gastrointestinal tract (GIT). In some people with Crohn’s disease, only the last segment of the small intestine (ileum) is affected. In others, the disease is confined to the colon (part of the large intestine). The most common areas affected by Crohn’s disease are the last part of the small intestine and the colon. Signs and symptoms of Crohn’s disease can range from mild to severe. They usually develop gradually, but sometimes will come on suddenly, without warning. You may also have periods of time when you have no signs or symptoms (remission). More than a half million Americans have been diagnosed with Crohn‘s disease. Crohn’s disease–related inflammation is segmental and transmural, leading to various degrees of tissue damage. At disease onset, most patients have inflammatory lesions, which become predominantly strictures or penetrating lesions over time.

Ulcerative colitis is a chronic disease that affects about 620,000 Americans. It causes inflammation and ulcers in the inner lining of the large intestine and is one of two main forms of chronic inflammatory bowel disease. The inflammation can lead to abdominal discomfort, gastrointestinal bleeding, and diarrhea.

“Ulcerative colitis and Crohn‘s disease are debilitating diseases that impact the quality of life of those who have these conditions,” said Amy G. Egan, M.D., M.P.H., acting deputy director of the Office of Drug Evaluation III in the FDA‘s Center for Drug Evaluation and Research.

When the disease is active, signs and symptoms may include:

  •  Diarrhea
  • Abdominal pain and cramping
  • Blood in your stool
  • Reduced appetite and weight loss
  • Fever and fatigue
  • Mouth sores etc.

People with severe Crohn’s disease may also experience:

  • Inflammation of skin, eyes and joints
  • Inflammation of the liver or bile ducts
  • Delayed growth or sexual development, in childrenAnti-inflammatory drugs are often the first step in the treatment of inflammatory bowel disease. These include:  Azathioprine and mercaptopurineThese are the most widely used immunosuppressants for treatment of inflammatory bowel disease. Short term, they also can be associated with inflammation of the liver or pancreas and bone marrow suppression. Long term, although rarely, they are associated with certain infections and cancers including lymphoma and skin cancer. They may also cause nausea and vomiting.Methotrexate This drug, which is used to treat cancer, psoriasis and rheumatoid arthritis, is sometimes used for people with Crohn’s disease who don’t respond well to other medications.


  • Infliximab, adalimumab and certolizumab pegol These drugs, called TNF inhibitors or “biologics,” work by neutralizing an immune system protein known as tumor necrosis factor (TNF). They are used for adults and children with moderate to severe Crohn’s disease to reduce signs and symptoms. They also may induce remission. Researchers continue to study these drugs to compare their benefits.
  • Corticosteroids A newer type of corticosteroid, budesonide works faster than do traditional steroids and appears to produce fewer side effects. However, it is only effective for Crohn’s disease that’s in certain parts of the bowel.
  • Oral 5-aminosalicylatesThese drugs have a number of side effects, including nausea, diarrhea, vomiting, heartburn and headache. These drugs have been widely used in the past but now are generally considered of limited benefit.
  • Treatment for Crohn’s disease usually involves drug therapy or, in certain cases, surgery. There is currently no cure for the disease, and there is no one treatment that works for everyone. By reducing the inflammation that triggers your signs and symptoms, it improves long-term prognosis by limiting complications. In the best cases, this may lead not only to symptom relief but also to long-term remission.

Vedolizumab (Entyvio ): It is approved to treat those conditions when one or more standard therapies have not resulted in an adequate response. The recommended dosage of vedolizumab in adults with ulcerative colitis or Crohn’s disease is 300 mg administered by intravenous infusion over 30 min at zero, two and six weeks and then every eight weeks thereafter.

Similar pharmacokinetics were observed in ulcerative colitis and Crohn’s disease patients administered 300 mg vedolizumab as a 30 minute intravenous infusion on Weeks 0 and 2, followed by 300 mg vedolizumab every eight weeks starting from Week 6. Population pharmacokinetic analyses indicated that the linear clearance was approximately 0.157 L/day, the serum half-life was approximately 25 days at 300 mg dosage, and the distribution volume was approximately 5 L.

The safety and effectiveness of vedolizumab for Crohn‘s disease were established in three clinical trials involving approximately 1,500 patients who had not responded adequately to corticosteroids, immunomodulators, or tumor necrosis factor blocker medications. Results showed that a greater percentage of participants treated with Entyvio compared to a placebo achieved clinical response, achieved clinical remission, and achieved corticosteroid-free clinical remission.

Under Investigation:

 Mongersen, an Oral SMAD7 Antisense Oligonucleotid; is a formulation containing a 21-base single-strand phosphorothioate oligonucleotide that hybridizes to the human SMAD7 messenger RNA (mRNA) and facilitates RNase H–mediated RNA degradation through a classic antisense mechanism. Mongersen is a modified-release tablet, designed to deliver the active substance primarily into the lumen of the terminal ileum and right colon.

Pharmacokinetic analysis of plasma before and after treatment suggested that mongersen was not systemically available. Drug acts locally, no systemic exposure. Therefore, it has better define the efficacy and safety for treating adults with active Crohn’s disease. The researchers found that 55 and 65% of patients in the 40mg and 160mg mongersen groups, respectively, reached the primary end point, compared with 10% of patients in the placebo group.

New Tuberculosis Treatment

TB Treatment

Tuberculosis (TB) caused from infection of Mycobacterium tuberculosis continues as a global epidemic. Third of the world population is at risk of developing active TB. Each year, 9 million patients are newly diagnosed with active TB and 2 million patients die of TB. The rapid spread of the human immunodeficiency virus (HIV) fueled the TB epidemic, especially in sub-Saharan Africa, where 28% of TB patients are HIV positive. The current first-line treatment for TB is a multidrug regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (RHZE). It must be taken for at least 6 months to achieve high cure rates (more than 95% in experimental settings).

Limitations associated with the currently available TB treatment are:

1) Duration and complexity of treatment result in nonadherence to treatment. This leads to suboptimal response (failure and relapse), the emergence of resistance, and continuous spread of the disease.

2) Adverse events in response to anti-TB drugs are common and contribute to the problem of nonadherence. The current first-line treatment for TB is a multidrug regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (RHZE). It must be taken for at least 6 months to achieve high cure rates (more than 95% in experimental settings).

3) Multidrug-resistant (MDR) -TB is defined as TB caused by M. tuberculosis strains that are resistant to, at least, the two most powerful first-line anti-TB drugs, isoniazid and rifampicin; extensively drug-resistant (XDR)-TB refers to a form of disease caused by strains of M. tuberculosis that are resistant to isoniazid and rifampicin, in addition to any fluoroquinolone, and to at least one of the three following injectable drugs: capreomycin, kanamycin or amikacin. Resistant TB occurs in the presence of partially suppressive drug concentrations that enable replication of bacteria, the formation of mutants, and overgrowth of wild-type strains by mutants (selective pressure). Mathematical models show that the MDR and XDR-TB epidemics have the potential to further expand, thus threatening all gains in TB control over recent decades.

The World Health Organization developed the directly observed therapy short course (DOTS) strategy to optimize response and adherence to TB treatment. However, DOTS is labor-intensive and expensive. It causes a high burden on public health programs, especially in developing countries with limited human resources. The rapid development of new anti-TB drugs has been hampered by several obstacles. First of all, the TB drug market is associated with insufficient profit opportunity or investment return to instigate pharmaceutical industries to develop new drugs.

New Drug:

TMC207 is a first-in-class diarylquinolone compound with a novel mechanism of action and potent activity against drug-sensitive and drug-resistant TB.

TMC207 has bactericidal and sterilizing activity against M. tuberculosis and other mycobacterial species but little activity against other bacteria. An EBA study in treatment-naive patients with pulmonary TB showed delayed, modest activity of the drug after 7 days, and a Phase II efficacy study conducted in patients with MDR-TB taking TMC207 plus an individualized background regimen showed impressive results after 2 months of treatment, with the results of a longer TMC207-based treatment course to follow. The drug appears to be safe and well tolerated, and development plans with the goal of an MDR-TB indication are well underway. the management of the over 500,000 cases of MDR-TB and XDR-TB would greatly benefit from availability of a new drug like TMC207, which is potent, well tolerated and structurally and mechanistically unrelated to current first-line TB drugs. Fortunately, given the product development partnership between Industry and the TB Alliance, both strategies (using TMC207 in shorter first-line regimens or using it in second line regimens for drug-resistant M. tuberculosis infections) are being pursued.

The maximum plasma concentration (Cmax) is reached after 5 h (Tmax). Average steady-state plasma concentration of 0.6 μg/ml form 8 weeks of treatment (400 mg daily dose for 2 weeks, followed by 200 mg three times a week for 6 weeks). It has an exceedingly long terminal half-life of 173 hr. It is metabolized by oxidative metabolism via cytochrome P450 isoenzyme CYP3A4. The majority of adverse events are of mild or moderate intensity. Nausea is significantly more frequently reported by patients treated with TMC207 in the MDR-TB trial. Diarrhea, arthralgia, dizziness, hyperuricemia and eye disorders are more frequent, but not of statistical significance. TMC207 produces increases in the QT interval, but no pathologically prolonged QT or corrected-QT values are observed. The clinical activity of TMC207 validates ATP synthase as a viable target for the treatment of tuberculosis.

Cystic Fibrosis: current treatments and newly (July 2015) approved therapy


Cystic fibrosis (CF) is known to cause your lungs to produce extra-thick, sticky mucus. This mucus builds up and clogs the airways and becomes a source of inflammation and infection that can lead to lung damage. As the white blood cells fight the infection caught in the mucus, they leave behind remains called extracellular DNA. The buildup of these remains makes the mucus in lungs affected by CF even thicker than before, leaving the lungs even more vulnerable to irreversible structural changes, progressive decline in function, and eventually respiratory failure. Disease severity for CF is based on lung capacity measured by spirometry pulmonary function tests such as forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC). Normal pulmonary disease is defined as FEV1 percentage of greater than 90% predicted, 70-89% predicted for mildly impaired, 40-69% predicted for moderately impaired, and an FEV1 percentage of less than 40% predicted is defined as severely impaired. Despite several supportive therapies; the median age of death is still 27 years. CF affects about 30,000 people in the United States and about 70,000 people globally.

CF is a serious genetic condition. It caused by reduced quantity and/or function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein due to mutations in the CFTR gene in CF patients. The CFTR protein is an epithelial chloride channel that aids in regulating salt and water absorption and secretion and pH balance in multiple organs, including the lungs, pancreas and other gastrointestinal organs, and sweat glands. Decreased CFTR chloride transport results in multisystem pathology, beginning at birth.  Salt loss may contribute to symptoms early in life and is the traditional diagnostic test for CF. Despite several supportive therapies; the median age of death is still 27 years.


For Infections:

  • Antibiotics (ciprofloxacin and tobramycin)

To open airways in the lungs or keep them open:

  • Bronchodilators (albuterol or salmeterol), which are used to make breathing easier. They may also make it easier to cough up mucus.
  • Anticholinergics (Atrovent)

To control the amount and thickness of mucus:

  • Pulmozyme is a purified solution for inhalation of recombinant human deoxyribonuclease (rhDNase) which reduces lung sputum viscosity and improves secretion clearance. Pulmozyme is recommended for the chronic treatment of moderate to severe CF pulmonary disease. The recommended dosage for use in most cystic fibrosis patients is one 2.5 mg single-use ampule inhaled once daily using a recommended jet nebulizer/compressor system or eRapid Nebulizer System. Most patients gain optimal benefit from regular daily use of Pulmozyme. In studies in which Pulmozyme was given in an intermittent regimen, improvement in pulmonary function was lost on cessation of therapy. Patients should therefore be advised to take their medication every day without a break.
  • Saltwater solution (hypertonic saline). This is sometimes used to help clear mucus from the lungs. It is low-cost, and it may help reduce inflammation in the airways.

To reduce inflammation:

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) (such as ibuprofen)
  • Membrane stabilizers (such as cromolyn)
  • Corticosteroids (such as fluticasone or prednisone)

With digestive enzymes:

  • Enzyme replacement therapy (such as Creon or Pancreaze)

With cystic fibrosis transmembrane conductance regulator (CFTR) potentiators:

  • Ivacaftor (CFTR), a potentiator, is used for treatment of CF in patients age 2 years and older who have the G551D mutation in the CFTR gene.

2-5 years, <14 kg: 50 mg granules PO q12hr before or after eating fat-containing food

2-5 years, ≥14 kg: 75 mg granules PO q12hr before or after eating fat-containing food

6-17 years: 150 mg PO q12hr before or after eating fat-containing food

 Dose needs to be reduced to 150 mg PO twice-a-week when co-administrating with strong or moderate CYP3A inhibitors. Co-administration with a strong CYP3A inducer, significantly decreased ivacaftor exposure (AUC) by approximately 9-fold. Therefore, co-administration with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John’s Wort is not recommended.

 This compound offers a novel approach to the treatment of CF, as it is the only marketed drug that targets the underlying cause of this lethal condition, instead of the downstream disease processes that occur as a result of lacking or defective CFTR. Available clinical trial data indicate that compared with placebo, ivacaftor has superior efficacy for improving respiratory function, and it has been shown to lower the risk of pulmonary exacerbations. The adverse-effect profile of ivacaftor does not differ substantially from placebo, but patients will need to be monitored for hepatic function and potential drug interactions during treatment.

 Newly approved therapy

If the patient is homozygous for the F508del mutation in the CFTR gene, needs a CFTR corrector with Ivacaftor (Lumacaftor/Ivacaftor (Orkambi), approved by FDA in July 2015. Lumacaftor corrects the processing and trafficking defect of the F508del-CFTR protein to enable it to reach the cell surface where the CFTR potentiator, ivacaftor, can further enhance the ion channel function of the CFTR protein. Ivacaftor facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR proteins. The combination is indicated for cystic fibrosis in patients aged 12 yr or older who are homozygous for the F508del mutation in the CFTR gene: ≥12 yr: 1 tablet (Lumacaftor/Ivacaftor: 200 mg/125 mg) PO q12hr with fat containing food. Study data show that lumacaftor in combination with ivacaftor provides benefit for patients with cystic fibrosis homozygous for the F508del CFTR mutation The most common side effects of Orkambi include shortness of breath, upper respiratory tract infection, nausea, diarrhea, and rash. Women who took Orkambi also had increased menstrual abnormalities such as increased bleeding.

Wearable, Noninvasive Devices for Parkinsons Disease

Device Sponsor Summary
Fall Detection SystemsD1 Phillips, GreatCall, etc. • Detect a fall

• Connect to Certified Response Agent

mPower AppD2 Sage Bionetworks, Unv. of Rochester, MJFRF • Track symptoms using memory game, finger tapping, speaking, walking

• Collect data from wearable device

Non-Invasive Galvanic Vestibular StimulatorD3 Unv. of Gothenburg, Sweden, collaboration with NASA • Target loss of motor control, tremors, stiffness

• Electrically stimulates vestibular system to improve balance

• Tested in both medicated and un-medicated patients; greater effect in un-medicated patients

BalanceWear® BW300D4 Motion Therapeutics, Inc., CA • Balance-Based Proprioceptive Neuromuscular Strategic Weighting Full Torso Device

• Flexible weights placed in garment based on Body Chart Weight Locator

• Improve the balance and stability

Mobile App


Roche •  Continuous measurement of disease fluctuation

•  Objective measures and realtime monitoring of Tx response by HCP

STIMbandD6 Johns Hopkins Unv. •3D printed device with electrodes, fits over a patient’s head

•Apply electrical stimulation to ease symptoms

Personal Kinetigraph (FDA cleared)D8 Global Kinetics Corporation • Collects data on movement

• Reminds patient to register levodopa ingestion

• Info sent to Physician; MAY lead to treatment decisions

CalibraceD10 AbiliLife • Increases postural stability by realigning shoulder and spine

• Functional, breathable, light; may prevent falls

Parkinson’s Disease : New Drugs in Development

The loss of dopamine-producing cells in the brain is an underlying issue in Parkinson’s disease.

Currently approved or in R&D medicines for Parkinson’s disease treat the symptoms of the disease, such as mobility problems and tremors, but do not replace lost nerve cells or halt the progression of the disease itself.

Several drugs in development are disease-modifying therapies focused on protecting brain cells in an attempt to halt disease progression, or treatments aimed at generating new cells or repairing damaged nerve cells.

Product Name Sponsor Indication Development Phase*

gene therapy


Cambridge, MA

University of California San Francisco

San Francisco, CA

Voyager Therapeutics

Cambridge, MA

Parkinson’s disease Phase I


levodopa/carbidopa intestinal gel



North Chicago, IL

advanced Parkinson’s disease

(Fast Track)

application submitted


gene therapy


Amsterdam, Netherlands

University of California San Francisco

San Francisco, CA

Parkinson’s disease Phase I



Acorda Therapeutics

Ardsley, NY

University of Miami

Miami, FL

Parkinson’s disease

(improve gait)

Phase I/II


(PDE4 inhibitor

The Michael J. Fox Foundation for

Parkinson’s Research

New York, NY

Sano_ US

Bridgewater, NJ

Parkinson’s disease Phase I


(myeloper-oxidase [MPO]



Wilmington, DE

Parkinson’s disease Phase II

BIA 9-1067



Coronado, Portugal

Parkinson’s disease Phase I completed


levodopa continuous infusion



Piedmont, CA

Parkinson’s disease Phase I

GM608 Genervon Biopharmaceuticals

Pasadena, CA

Parkinson’s disease Phase II


(MOA-B inhibitor

Dart NeuroScience

San Diego, CA

Parkinson’s disease Phase I

IPX203 Impax Pharmaceuticals Hayward, CA Parkinson’s disease Phase II
istradefylline (KW-6002) Kyowa Hakko Kirin Pharma Princeton, NJ severe Parkinson’s disease Phase III
levodopa inhalation (CVT-301) Civitas Therapeutics Chelsea, MA Parkinson’s disease (adjunctive therapy) Phase II
LY03003 (rotigotine extended-release microsphere formulation) Luye America Pharmaceuticals Princeton, NJ Parkinson’s disease (early-stage disease) Phase I
OS-320 (levodopa/carbidopa) Osmotica Pharmaceutical Wilmington, NC Parkinson’s disease Phase III
P2B001 (pramipexole/rasagiline ­ xed-dose combination) Pharma Two B Rehovot, Israel Parkinson’s disease (early-stage disease) Phase II
Phosphen® R-phenserine QR Pharma Berwyn, PA Parkinson’s disease Phase II
Rytary™ levodopa/carbidopa extended release Impax Pharmaceuticals Hayward, CA idiopathic Parkinson’s disease application submitted
safinamide Newron Pharmaceuticals Bresso, Italy early-stage Parkinson’s disease (adjunctive therapy)

——————————— late-stage and mid-stage Parkinson’s disease (adjunctive therapy)

Phase III

———————————— Phase III

tozadenant (SYN-115) Biotie Therapies South San Francisco, CA UCB Brussels, Belgium Parkinson’s disease (adjunctive therapy) Phase II/III
V81444 Vernalis Winnersh, United Kingdom Parkinson’s disease Phase I/II
vatiquinone Edison Pharmaceuticals Mountain View, CA Parkinson’s disease Phase II
XP21279 XenoPort Santa Clara, CA Parkinson’s disease Phase II
Florbenazine (18F-AV-133) Eli Lilly Indianapolis, IN Parkinson’s disease (diagnosis) Phase II


(123-I labeled imaging agent)

Navidea Biopharmaceuticals Dublin, OH Parkinsonian disorders (diagnosis) Phase III
NuroPro® neurotrophic factor companion diagnostic Amarantus BioScience San Francisco, CA Parkinson’s disease (diagnosis) Phase I
Parkinson’s Disease—Related Conditions
ADS-5102 (amantadine controlled release) Adamas Pharmaceuticals Emeryville, CA levodopa-induced dyskinesia Phase II/III
AQW051 (alpha7 nicotinic receptor) Novartis Pharmaceuticals East Hanover, NJ Levodopa-induced dyskinesia Phase II completed
AVP-923 (dextromethorphan/quinidine) Avanir Pharmaceuticals Aliso Viejo, CA Levodopa-induced dyskinesia Phase II

camicinal (motilin receptor agonist) GlaxoSmithKline , PA gastroparesis in Parkinson’s disease Phase II
dipraglurant-IR (ADX48621) Addex Therapeutics Geneva, Switzerland Levodopa-induced dyskinesia Phase II
eltoprazine Amarantus BioScience San Francisco, CA Levodopa-induced dyskinesia Phase II


Malaria Vaccine: Current Status


Malaria occurs in nearly 100 countries worldwide, exacting a huge toll on human health and imposing a heavy social and economic burden in developing countries, particularly in Sub-Saharan Africa and South Asia. An estimated 207 million people suffered from the disease in 2012, and about 627,000 died. About 90 percent of the deaths were in Sub-Saharan Africa, and 77 percent were among children under age 5.

It is transmitted among humans by female mosquitoes of the genus Anopheles. Female mosquitoes take blood meals to carry out egg production, and such blood meals are the link between the human and the mosquito hosts in the parasite life cycle.  The parasite Plasmodium, a single-celled organism that has multiple life stages and requires more than one host for its survival. Five species of the parasite cause disease in humans – Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and P. knowlelsi. Plasmodium falciparum is the most dangerous strain in humans and the target of most scientific research today.

Malaria symptoms are high fever, chills, flu-like symptoms, and severe anemia. These symptoms can be especially dangerous for pregnant women and young children who are experiencing the disease for the first time. Severe malaria can cause lifelong intellectual disabilities in children, and malaria’s economic impact is estimated to cost billions of dollars in lost productivity every year.

Calling the Ebola epidemic a “critical moment in the history of global health,” Bill Gates, Co-chair of the Bill & Melinda Gates Foundation (PATH Malaria Vaccine Initiative), urged greater investment in scientific innovation to ensure that the world stays ahead of rapidly evolving disease threats such as drug-resistant malaria and dengue fever.

Addressing the annual meeting of the American Society of Tropical Medicine and Hygiene, Gates announced that the foundation is committing more than $500 million to reduce the burden of malaria, pneumonia, diarrheal diseases, and an array of parasitic infections that are leading causes of death and disability in developing countries. Gates also announced that the foundation has boosted its annual funding for malaria by 30 percent, and he laid out a vision for how malaria can be eradicated by the middle of the 21st century.

World’s first malaria vaccine, backed by Bill Gates, received a green light for future use in babies in sub-Saharan Africa. GlaxoSmithKline worked with the PATH Malaria Vaccine Initiative to develop the vaccine, which was called RTS,S when it was experimental and which now has the brand name Mosquirix. The European Medicines Agency has OK’d it for use in children 6 weeks to 17 months old.Jul 24, 2015.

Mosquirix. is the most advanced vaccine candidate against the most deadly form of human malaria, Plasmodium falciparum. A Phase III trial began in May 2009 and has completed enrolment with 15 460 children in the following seven countries in sub-Saharan Africa: Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique, and the United Republic of Tanzania. The World Health Organization lists malaria as the fifth biggest killer in sub-Saharan Africa.

There are two age groups in the trial: 1) children aged 5-17 months at first dose receiving only the RTS,S/AS01 vaccine; and 2) children aged 6-12 weeks at first dose who receive the same malaria vaccine co-administered with pentavalent vaccines in the routine immunization schedule. Both groups receive 3 doses of Mosquirix. vaccine at 1 month intervals.

The final Phase III results were published in April 2015. The vaccine will be evaluated as an addition to, not a replacement for, existing preventive, diagnostic and treatment measures. The need for long-lasting insecticidal nets, rapid diagnostic tests and artemisinin-based combination therapies will continue if Mosquirix. becomes available and is used. It prevented a substantial number of cases of clinical malaria over a 3–4 year period in young infants and children when administered with or without a booster dose. Efficacy was enhanced by the administration of a booster dose in both age categories. Thus, the vaccine has the potential to make a substantial contribution to malaria control when used in combination with other effective control measures, especially in areas of high transmission.

STORYLINE:  Drug-resistant malaria is viewed as an epidemic in developing countries. Vaccines being developed and approved to curb the spread of malaria. Vaccines will complement the existing therapies and preventive measures.

malaria vaccine development

Vaccine candidate shows efficacy against Dengue


Dengue is caused by four distinct virus serotypes transmitted by mosquitoes. It is a threat to nearly half of the world’s population. Currently, there is no specific treatment available for dengue. It is a health priority in many countries of Latin America and Asia where epidemics occur regularly.

The yellow fever mosquito can spread the dengue fever and yellow fever viruses, and other diseases. The mosquito is a small, dark mosquito of approximately 4 to 7 millimeters with typical white markings on the legs and a marking of the form of a lyre on the thorax. Dengue is transmitted by a mosquito bite that could cause infection of one of four dengue virus (DENV) serotypes, known as DENV1-4.

Symptoms of dengue include fever, severe headache, joint pain, muscle and bone pain, severe pain behind the eyes and mild bleeding – such as nose bleed. A more severe form of the virus is known as dengue hemorrhagic fever, characterized by prolonged fever, abdominal pain, persistent vomiting, bleeding and breathing problems. According to the World Health Organization, more than 22,000 people worldwide die from dengue each year, the majority of whom are children. Dengue is underreported because the disease is often misdiagnosed due to a large spectrum of clinical symptoms from mild non-specific illness to life threatening complications and because of the limitations of the surveillance systems.
Sanofi Pasteur’s dengue vaccine candidate is the most clinically and industrially advanced vaccine candidate in development. Two pivotal Phase III efficacy studies involved more than 31,000 volunteers from Asia (Indonesia, Malaysia, the Philippines, Thailand and Vietnam) and Latin America (Brazil, Colombia, Honduras, Mexico and Puerto Rico). The Phase III trials provided pivotal data on efficacy, safety, and immunogenicity of the vaccine candidate in a broad population and different epidemiological environments and assess the potential public health impact of the vaccine on the disease burden.
“The results of this first phase III study show the potential of the vaccine to have a significant impact on public health,” commented Dr. Maria Rosario Capeding, study principal investigator, Research Institute for Tropical Medicine, the Philippines. “The threat of severe dengue disease creates fear in the community. The vaccine’s impact on preventing dengue hemorrhagic fever is noteworthy. A vaccine that is able to avoid the personal suffering and reduce this significant health burden would change the lives of millions.”

“The high efficacy observed against severe dengue and the reduction of hospitalization by two thirds is an extremely important public health outcome. Furthermore this dengue vaccine continues to meet the highest safety expectations, which is very reassuring,” commented Professor Duane Gubler, Professor and Founding Director of the Signature Research Program on Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, and Chairman of the Partnership for Dengue Control.

Pooled vaccine efficacy against dengue of any severity and any serotype from the efficacy surveillance phase among participants who were 9 years of age or older was 65.6%; pooled vaccine efficacies for serotype-specific dengue were all higher than the nonpooled vaccine efficacies. On the basis of a limited number of participants in the immunogenicity subgroups, pooled analyses of data from participants who were 9 years of age or older showed that the vaccine efficacies were 81.9% (95% CI, 67.2 to 90.0) among seropositive participants and 52.5% (95% CI, 5.9 to 76.1) among seronegative participants

Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease” study report can be found in the New England J Med link (July 27, 2015)

Current status of Ebola Vaccine research


Experimental Ebola vaccine tested on thousands of people and might help shut down the waning epidemic in West Africa. Merck, Johnson & Johnson and GlaxoSmithKline already have their candidates in mid-stage trials. Novavax completed Phase I trial.


Merck stated that its investigational Ebola vaccine candidate, rVSV-ZEBOV, was found to have 100 percent efficacy based on an interim data analysis from a Phase 3 ring vaccination trial in Guinea. The authors report that vaccine efficacy was 100 percent (95% confidence interval: 74.7 – 100%; p=0.0036) following vaccination with a single dose of the rVSV-ZEBOV vaccine.

In late 2014, when the current Ebola outbreak was at its most severe, Merck was licensed rVSV-ZEBOV from NewLink Genetics Corporation. Vaccinated individuals developed antibodies against the Ebola virus, which would help protect against future infection. It appeared that all vaccinated individuals were protected against Ebola virus infection within 6 to 10 days of vaccination. To date, the rVSV-ZEBOV vaccine has been administered to more than 9,000 people in phase 1, 2 and 3 clinical trials. The significance and durability of this immune response have not been determined.

GSK and J&J/Bavarian Nordic

GlaxoSmithKline recently reported positive results from the Liberian Phase II trial of its candidate and that it may advance to Phase III. Johnson & Johnson announced in March that it was ready to start trialing its vaccine candidate in Ghana, Tanzania and Kenya.


Novavax took its Ebola vaccine candidate to Australia for a Phase I trial. The company reported positive top-line results from the 230-person trial. The ebolavirus glycoprotein recombinant nanoparticle vaccine, or Ebola GP vaccine for short, was well-tolerated and provoked high ebolavirus antibody responses, said Dr. Greg Glenn, Novavax’s research chief, in a statement.

“We’re not at the same stage as some of the other developers … but what we have is an improvement over what’s already being tested,” Glenn said, as quoted by Reuters. If all goes well, the vaccine could be market-ready in two to three years, he said.


Health workers in Guinea check the blood pressure and other vital signs of a man about 30 minutes after he was given the trial Ebola vaccine. Photo by WHO

ASCO 2015 Highlights

ASCO ASCO Annual Mtg

The 51st ASCO Annual Meeting took place in Chicago May 29 – June 2, brought together more than 30,000 oncology professionals from a broad range of specialties from around the world. This year’s Annual Meeting was focused on the theme of Innovation and Illumination, pointing to the potential for integrating cancer science and health information technology to achieve more rapid improvements in patient care. Along with new research,

ASCO President Peter Yu, MD stated at the meeting, “We are in an information age and there is a lot of data coming at us. We need to become smarter and more nimble about how we look at data and derive knowledge, and then that drives actual decision-making that improves patient outcomes.”

Prostate Cancer Foundation’s a few highlights for patients

Upfront Therapy with Docetaxel Prolongs Overall Survival in Men with Hormone-Naïve Metastatic Prostate Cancer Commencing Androgen Deprivation Therapy: First survival results from STAMPEDE: Dr. Nicholas James, University of Warwick and Queen Elizabeth Hospital Birmingham.

Dr. Nicholas James presented the first survival results released from the STAMPEDE clinical trial, which tested the outcome of adding various therapies to standard of care (SOC) consisting of androgen deprivation therapy (ADT) with or without radiotherapy (RT), in hormone-naïve patients either presenting with metastatic disease or relapsing after prostatectomy or RT. Results were presented from four randomized study arms: SOC (1184 patients), SOC + zoledronicacid (593 patients), SOC + docetaxel + prednisolone (592 patients), and SOC + zoledronicacid + docetaxel + prednisolone (593 patients). No benefits to failure free survival (FFS) or overall survival (OS) were observed with addition of zoledronicacid, a bisphosphonate that reduces bone fractures and pain from bone metastases. The addition of docetaxel + prednisolone to SOC extended median FFS from 21 months to 37 months and extended median OS from 67 months to 77 months. These results supported previous results from the CHAARTED trial where a median overall survival (OS) improvement from 44 to 57.6 months with the addition of docetaxel to ADT in hormone-sensitive metastatic prostate cancer patients was observed. Collectively, these results supported a paradigm change in clinical practice. Docetaxel in combination with ADT should now be considered much earlier in the treatment regimen for men with hormone-naïve metastatic prostate cancer.

Neoadjuvant Chemotherapy Combined with ADT and IMRT Shows Survival Benefit in Localized High-Risk Prostate Cancer Patients: Results from RTOG 0521. Dr. Howard Sandler, Cedars-Sinai Medical Center

Dr. Howard Sandler presented results from RTOG 0521, a Phase III trial testing the addition of docetaxel + prednisone to ADT+ Intensity-Modulated RT (IMRT) in treatment-naïve high-risk localized prostate cancer. At a median of 6 years of follow up, 563 patients were evaluable. The addition of docetaxel + prednisone to ADT + IMRT improved the 4-year overall survival (OS) rate from 89% to 93% of patients and improved 6-year disease-free survival rates from 55 to 65%. These studies indicated that neoadjuvant chemotherapy in combination with ADT and IMRT may benefit patients with localized high-risk prostate cancer and should be considered as the first line of therapy. These studies indicate that neoadjuvant chemotherapy in combination with ADT and IMRT may benefit patients with localized high-risk prostate cancer and should be considered as the first line of therapy.

Genomic Analysis of Circulating Cell-free DNA Identifies Mechanisms of Primary and Acquired Resistance to Enzalutamide in Metastatic Castration-Resistant Prostate Cancer (mCRPC). Dr. Arun Azad, BC Cancer Agency, Vancouver, Canada

Dr. Arun Azad (BC Cancer Agency, Vancouver, Canada) and colleagues assessed genomic alterations in cfDNAfrom metastatic castrate resistant prostate cancer (mCRPC) patients prior to and following the development of resistance to treatment with enzalutamide.Poorer median progression-free survival (mPFS) in response to enzalutamide was associated with pre-existing copy-number amplifications of the oncogenes AR, MYC and MET, mutations in AR, or copy-number losses of the tumor-suppressor gene RB1. Ten of 44 patients acquired new copy-number changes during enzalutamide treatment. Acquired AR or MYC amplifications or RB1-loss were associated with poorer mPFSduring treatment with enzalutamide. Five patients acquired new AR mutations during enzalutamide treatment and also had significantly reduced mPFS. Ongoing studies are assessing tumor genomic alterations in patients enrolled in clinical trials with other therapies. These studies will lead to the establishment of Precision Medicine treatment models, in which tumor genomic profiles are used to select treatments most likely to provide benefit and avoid treatments for which benefit is unlikely.

Statin Use at the Time of Initiation of Androgen Deprivation Therapy Delays Time to Progression in Patients with Hormone-Sensitive Prostate Cancer. Dr. Lauren Harshman, Dana-Farber Cancer Institute, Harvard Medical School.

Dr. Lauren Harshman and colleagues hypothesized that the use of statins may boost the efficacy of androgen deprivation therapy (ADT) by competing with DHEAS for SLCO2B1 uptake and thereby further limiting the amount of androgens available to fuel prostate cancer cells. In a retrospective analysis of 926 analyzable patients who initiated ADT between 1996 and 2013, statin use at the time of ADT initiation was associated with a significantly increased median time to progression on ADT (27.5 months for statin users vs. 17.4 months for non-statin users). These differences were observed regardless of whether patients had radiographic evidence of metastasis or only biochemical relapse at the time of ADT initiation. These results require validation in a prospective study and further studies are needed to definitively define the mechanisms involved. Nevertheless, statins have an established safety profile and may be an effective anti-cancer therapeutic in combination with ADT

Other Hightights

The Saturday, May 30, Education Session of “Introduction to Methods in Comparative Effectiveness Research,” chaired by Sharon H. Giordano, MD, MPH, of The University of Texas MD Anderson Cancer Center, provided an overview of a variety of approaches to comparative effectiveness research (CER).

“A lot more people are starting to conduct research in this area,” Dr. Giordano said. “There has been a general realization that, although it would be ideal to do a randomized clinical trial for every situation in every population, it is not realistic, and because of those gaps in knowledge, people are interested in using comparative effectiveness research to help determine the best way to treat their patients. The purpose of CER is to assist consumers, clinicians, purchasers, and policy makers to make informed decisions that will improve health care at both the individual and population levels.”

Natasha K. Stout, PhD, of Harvard Medical School and Harvard Pilgrim Health Care Institute, discussed the use of disease simulation modeling in CER. Disease simulation modeling is an Institute of Medicine -endorsed methodology that helps to fill evidence gaps left by clinical trials or observation studies. According to Dr. Stout, models can often be used in cases in which a decision needs to be made immediately but for which traditional research would take years to produce an outcome of interest. Modeling can project both near- and long-term outcomes in a timely manner, and, in some cases, can project the value of conducting more research in a given area.

PK poster presentation:

PK of the chimeric anti-GD2 (ch14.18) antibody in children with high-risk neuroblastoma: Children’s Hospital of Philadelphia, PA and United Therapeutic Corp,, RTP, NC

Ch14.18 is a Chimeric Monoclonal Antibody (cMoAb), improves survival in high-risk neuroblastoma according previously reported study. Ch14.18 disposition was highly variable in children. Infusion dose was of 25 mg/m2 over 10 h to male (n-6) and female (n=4) children of 1 to 7 yr old. Mean Cmax, half-life (HL) clearance (CL) and volume distribution (Vd) were 14 mcg/mL, 260 hr, 11 mL/h/m2 and 2.8 L/m2, respectively. C14.18 CL, Vd and HL in children were similar to those in adults at same dose level.


2015 BIO International Convention


The Department of Community and Economic Development welcomed the 2015 BIO International Convention, June 15-18 at Pennsylvania Convention Center, Philadelphia, hosted by the Biotechnology Industry Organization. More than 15,000 leaders from 69 countries and 49 states were participated.

Here are highlights:

Keynote Speaker Tom Brokaw (on June 16)

Brokaw described his observations on the state of the U.S. and the world with important political headlines, economic challenges and social issues in the news—and the people behind the headlines. He mentioned about the challenges that face America in the new millennium and offered reflections on how we can restore America’s greatness. In 2014, President Obama awarded Brokaw with the Presidential Medal of Freedom.

He talked to Dr. Oz, in an interview, about beating multiple myeloma with a nagging back pain. Multiple myeloma is a cancer formed by malignant plasma cells. Brokaw said “what happens is that the white blood cells invade the bone marrow.” His cancer is now in remission, although he is still dealing with some bone damage that comes with this type of cancer. As a result he had some unexpected fractures in his back and in pelvic area but they’re beginning to heal.

Keynote Speaker Dr Eric Topol (on June 17)

Dr. Eric Topol mentioned the importance of the Precision Medicine Initiative as a way to further revolutionize how we improve health and treat disease with early diagnostic and personalized treatment.

He mentioned, in partnership with the Wireless-Life Sciences Alliance, the Digital Health program would explore the intersection of digital health, biotech and pharma. Industry thought leaders, stakeholders and innovators would highlight digital health’s role in drug development, clinical trials, medication compliance, prescribable apps, new business models, big data and much more.


Start-ups get chance to shine at BIO convention

This year’s event attracted close to 16,000 industry leaders to Philadelphia, as well as Mayor Nutter, Gov. Wolf, and other government and civic leaders. Mayor said, “As home to an extraordinary lineup of education, health, and biotech-related organizations, our region set the tone for the high-energy buzz.”

One of the most exciting events of BIO was the Start-Up Stadium, which gave seed-stage companies the opportunity to pitch to potential investors, venture philanthropy groups, and other attendees from across the country and around the world. In the style of the popular Shark Tank TV show, the judges provided live feedback and interacted directly with the 30 start-up business owners, almost all of whom were based in Pennsylvania, New Jersey, or Delaware.

The innovative products that were showcased ranged from digital-health solutions to new methods of DNA testing and unique therapy delivery options.

The founder of Biomeme conducted a live demonstration of a testing device that enables health and government authorities to treat the sick and protect the healthy by using a hand-held device that lets them isolate and detect DNA and RNA in under an hour.

Another innovation on display was DenovoNow, a mobile platform that increases patient engagement by enhancing and further personalizing a patient’s relationship with his or her doctor at no additional cost to either party.

The other cutting-edge pharmaceutical and therapeutic treatments presented included a product developed by InteguRx Therapeutics described about one of their product that delivers once-daily anti-nausea treatment in a very small dose via a gel or patch to treat pregnancy-induced nausea and vomiting.

With the large pharmaceutical companies and biotech firms starting to look more to external sources for the next wave of innovation, the sessions were very well-attended. The investor community remains key to the success of these companies, and the Start-Up Stadium attracted investor judges from groups such as the Bill & Melinda Gates Foundation, New Enterprise Associates, Bristol-Myers Squibb, Flagship Vetnures, J&J Innovation Center, and Roth Capital Partners.

 Complexities of Rare Diseases Take the Spotlight at BIO

Nicole Boice, Global Genes Founder, addressed the BIO 2015 Orphan & Rare Disease Track by saying: “We’re all working to eliminate the challenges of rare diseases, but patients and their advocates aren’t always equipped to fight.” Organizations like Global Genes helped families affected by rare disease by connecting them with much needed tools and resources.

He said, “Understanding the distinctions is an important part of understanding the state of the orphan drug development worldwide, both where it’s going and where it needs to go. However, the various stakeholders involved in the development and administration of orphan drugs tend to define rare diseases differently. Regulators define rare diseases by the number of patients affected, FDA defines a rare disease as affecting less than 200,000 Americans per year.. Most importantly, for patients the concept of “rare” can manifest itself as isolation from others, which is a problem that industry should address as it also seeks to develop innovative orphan drugs. However, when taken together, rare diseases as a whole affect a large number of patients worldwide.”

 Can Vaccination, Diagnostics Help to Combat Antibiotic Resistance?

Resistance to antibiotics and other antimicrobials is growing worldwide, with deaths from resistant infections at about 700,000 per year, and estimated to rise to 10 million per year by 2050.

“The problem is so serious that it threatens the achievements of modern medicine,” the World Health Organization (WHO) wrote in a recent report. In late May, the WHO formally endorsed an international plan, which calls for all member states to have national plans in place by May 2017 to stop the growth of resistant germs globally. A major component of the plan is to develop novel antibiotics, but strengthening surveillance of these drugs is of utmost importance.

“Vaccines are not the solution, obviously, but this is an ‘all hands on deck’ problem,” said Bruce Gellin, deputy assistant secretary for health and director of the National Vaccine Program Office at the BIO International Convention 2015 in Philadelphia. “And vaccines need to be a part of the discussion.”

Targeting pathogens with antibiotic-resistant strains

 In 2005, a vaccine for Staph infection by Nabi Biopharmaceuticals failed to reduce infections among kidney patients in late-stage trials. Staph infections, caused by staphylococcus bacteria, can turn life-threatening if bacteria invade the bloodstream, joints, bones, lungs or heart. Treatment usually involves antibiotics and drainage of the infected area; however, some staph infections no longer respond to common antibiotics.

“It set the field back,” said Charles Knirsch, MD, MPH, vice president, therapeutic vaccines program lead, Vaccine Clinical Research and Development at Pfizer, referring to the failure of the single-antigen vaccine called StaphVax.

Currently, Pfizer is helping to usher in a new era of vaccine innovation — both to prevent and treat disease. Specifically, the company is working on a vaccine for methicillin-resistant Staphylococcus aureus (MRSA), the leading cause of hospital-acquired infections. MRSA infects an estimated 53 million people globally, and in the U.S. alone, MRSA kills 20,000 people each year. But rather than focus on a single target, Pfizer’s new approach, said Knirsch, contains four vaccine components to generate a broad immune response. “Sometimes, it’s more art than science getting those conjugates right, and we’ve been able to do it so far with these widely sharing antigens,” said Knirsch. “Because of the recurrent nature of this disease, we believe the vaccine would work like the pneumococcal vaccine, and reduce overall use of antibiotics.” Pfizer recently began enrollment in a Phase 2b clinical trial evaluating its investigational Staphylococcus aureus multi-antigen vaccine in adult patients undergoing spinal fusion surgery. Competitors, including GlaxoSmithKline, Novartis and Sanofi are also investigating Staphylococcus aureus vaccines.

Role and complexity of infectious disease diagnostics development

Inappropriate use, a reason for the rise in antibiotic resistance, includes starting patients on antibiotics before test results come back, putting them on a broad-spectrum antibiotics when it’s unknown what bacteria is causing an infection, or keeping them on medications even when tests come back negative.

“As a diagnostics company, how do we approach this paradigm?” asked Tom Lowery, Ph.D., chief scientific officer at T2 Biosystems in Lexington, Mass. Currently, a blood culture can take two to six days to process and what’s more, a blood culture often misses 50 percent to 60 percent of bloodstream and tissue-based infections, said Lowery. “Today, with the diagnostic paradigm, there’s a lot of guesswork, and with the significant delay, patients get put on broad-spectrum antibiotics unnecessarily.”

A solution? “Highly-sensitive, rapid tests that can give not only species identification but resistance identification within the first three to five hours,” said Lowery.

In that vein, T2 Biosystems’s FDA-approved diagnostic is the first sepsis pathogen diagnostic panel requiring no blood culture that identifies with 91.1 percent sensitivity the five clinically relevant species of Candida “directly from whole blood which enables physicians to initiate appropriate therapy on day zero,” according to the T2 Biosystems website. Candida is the most common cause of fungal infections worldwide.

Said Lowery, “This represents a new class of diagnostic test that can have the same, or better sensitivity, as blood cultures and deliver those results rapidly so that a clinician can put a patient directly on the targeted therapy that he should be on right away, without this waiting time, without this inappropriate therapy that can drive mortality rate up.”


Storyline: The 2015 BIO spanned a range of topics from classics such as rare disease complexities, antibiotics resistance to the innovatives such as Digital Health Solutions and Start-Up stadium. This was topped by having Tom Brokaw and Eric Topol  as the keynote speakers.

Google developing a nanoparticle pill for detection of cancer and other diseases

The pill will identify cancers and other diseases before they become a problem. The pill contains magnetized nanoparticles attached with antibodies or other proteins are specific for the disease biomarker such as cancer or other diseases. These magnetized particles can be called back to a particular site to deliver their results. The data would then be collected by a wrist-worn smart device. This could lead to fast, painless diagnosis. Detail can be found in link below:

Google’s Wristband for Health Tracking

Google’s research division unveiled a new sensor-packed wristband, a medical device, to monitor the vital signs (pulse measuring, heart rhythm and skin temperature). It can also quantify environmental factors such as light exposure and noise levels. Google X can be used in clinical trials or as a doctor-to-patient communication tracking tool. Device could help doctors to get a complete picture of patients’ health related activity, when they are not coming for an examination. It is currently up for test its accuracy in trials. Google will be seeking regulatory approval on both sides of the Atlantic. Detail can be found in Bloomberg:

First approved pediatric lopinavir/ritonavir oral pellets for the treatment of AIDS in infants and young Children

Cipla Limited (Mumbai, India) announced that Co. received US FDA approval for an innovative formulation – Lopinavir/ritonavir for pediatric specific treatment for infants. According to the article, globally 3,200,000 children were living with HIV in 2013 and 240,000 children were newly infected with HIV. Although antiretroviral therapy can be life saving for these children, only 24% are currently on treatment. One third of the children born with HIV without treatment die before their first birthday and 50% die before they turn two. Detail can be found in the link:

Herbs pill to beat Anxiety

Three natural herbs in the A2X compound work together to aid body’s natural defense against anxiety. Ashwagandha, L-Theanine, and Passion Flower have been clinically proven to boost gamma-aminobutyric acid (GABA) and serotonin levels in the human body. GABA is a biologically active substance found in some plants. It is a neurotransmitter that inhibits activation of neurones. Studies have shown that these natural ingredients can stimulate the production of GABA. A2X treatment, over time, helps to calm body’s natural response to anxiety. Side effects from prescription medication are worse than the anxiety problem itself. A2X effectiveness reported to be safe for long-term use with no side effects.  Detail can be found in the link:

Habitual chocolate consumption could reduce the risk of cardiovascular disease

Authors in a study examined the association between chocolate intake and the risk of future cardiovascular events in total of 20951 men and women. Authors evaluated chocolate consumption and cardiovascular outcomes. Results suggested that higher chocolate intake is associated with a lower risk of future cardiovascular events. There does not appear to be any evidence to say that chocolate should be avoided in terms of cardiovascular risk. Detail is in attached link from Heart Journal (an official journal of the British Cardiovascular Society):

Chocolate is for medicinal use to treat age-related memory loss (Dementia)

Mars Inc., maker of M&M’s, Snickers and other candies, discussing with large pharmaceutical companies about developing a line of prescription medicines to treat a variety of illnesses including age-related memory loss, according to an article in the Washington Post. This could be due to cocoa-flavanol consumption. Researchers from Harvard, the UC-Davis and European universities presented papers on the relationship between cocoa-flavanol consumption and increased cerebral blood-flow.  Mars opinion is that cocoa flavanols could increase blood flow and help fight diseases such as age-related memory loss. According to Mars, several drug companies showed interest in developing drugs that use the medicinal properties of cocoa.