EXONDYS 51 (Eteplirsen) intravenous injection

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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. 

Mechanism of Action Eteplirsen is designed to bind 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 leads to the peak plasma concentrations (Cmax) of eteplirsen occurred 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 of EXONDYS 51 in male pediatric Duchenne muscular dystrophy (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 eteplirsen Cmax and AUC range from 20 to 55%, respectively.

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

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

 Elimination half-life (t1/2) of eteplirsen was 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.

Source: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206488lbl.pdf

 


DARZALEX (daratumumab) injection, for intravenous use

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 INDICATION: Treatment of patients with multiple myeloma

Mechanism of Action CD38 (cluster of differentiation 38) is a transmembrane glycoprotein (48 kDa) expressed on the surface of hematopoietic cells, including multiple myeloma and other cell types, and tissues and has multiple functions, such as receptor mediated adhesion, signaling, and modulation of cyclase and hydrolase activity. Daratumumab is an IgG1k human monoclonal antibody (mAb) that binds to CD38 and inhibits the growth of CD38 expressing tumor cells by inducing apoptosis directly through Fc mediated cross linking as well as by immune-mediated tumor cell lysis through complement dependent cytotoxicity (CDC), antibody dependent cell mediated cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). Myeloid derived suppressor cells (MDSCs) and a subset of regulatory T cells (CD38+Tregs) express CD38 and are susceptible to daratumumab mediated cell lysis.
Pharmacodynamics (PD) NK (Natural killer) cells express CD38 and are susceptible to daratumumab mediated cell lysis. Decreases in absolute counts and percentages of total NK cells (CD16+CD56+) and activated

(CD16+CD56dim) NK cells in peripheral whole blood and bone marrow were observed with DARZALEX treatment. CD4+ and CD8+ T cell absolute counts, as well as their percentage of total lymphocytes, increased with DARZALEX treatment in both the peripheral blood and bone marrow.

 DARZALEX as a large protein has a low likelihood of direct ion channel interactions. There is no evidence from non-clinical or clinical data to suggest that DARZALEX has the potential to delay ventricular repolarization.

Pharmacokinetics (PK) The PK of daratumumab following intravenous administration were evaluated in patients with relapsed and refractory multiple myeloma at dose levels from 0.1 mg/kg to 24 mg/kg, and included the recommended 16 mg/kg dose and regimen.

 Over the dose range from 1 to 24 mg/kg, increases in area under the concentration-time curve (AUC) were more than dose proportional. Clearance decreased with increasing dose and repeated dosing, indicating target-mediated pharmacokinetics.

 Following the recommended schedule and dose of 16 mg/kg, the mean [standard deviation (SD)] serum Cmax value was 915 (410) μg/mL at the end of weekly dosing, approximately 2.9-fold higher than following the first infusion. The mean (SD) predose (trough) serum concentration at the end of weekly dosing was 573 (332) μg/mL.

PK-PD Analysis  Not reported.
Population PK Based on the population PK analysis, daratumumab steady state is achieved approximately 5 months into the every 4-week dosing period (by the 21st infusion), and the mean (SD) ratio of Cmax at steady-state to Cmax after the first dose was 1.6 (0.5). The mean (SD) linear clearance and mean (SD) central volume of distribution are estimated to be 171.4 (95.3) mL/day and 4.7 (1.3 L), respectively. The mean (SD) estimated terminal half-life associated with linear clearance was approximately 18 (9) days.

Population PK analyses indicated that the central volume of distribution and clearance of daratumumab increase with increasing body weight, supporting the body weight-based dosing regimen. Population PK analyses also showed that age (31 to 84 years) and gender do not have clinically important effects on the pharmacokinetics of daratumumab.

Special Populations The population PK analysis included 71 patients with normal renal function (creatinine clearance [CrCL] ≥ 90 mL/min), 78 patients with mild renal impairment (CrCL <90 and ≥ 60 mL/min), 68 patients with moderate renal impairment (CrCL <60 and ≥ 30 mL/min) and 6 patients with severe renal impairment or end stage renal disease (CrCL <30 mL/min). No clinical differences in exposure to daratumumab were observed between patients with renal impairment and those with normal renal function.

 The population PK analysis included 189 patients with normal hepatic function (TB and AST≤ULN and 34 with mild hepatic impairment (TB 1.0x to 1.5x ULN or AST>ULN) patients. No clinical differences in the exposure to daratumumab were observed between patients with mild hepatic impairment and those with normal hepatic function. Daratumumab has not been studied in patients with moderate (TB>1.5x to 3× ULN and any AST) or severe (TB>3× ULN and any AST) hepatic impairment.

Drug Interactions None 

Source: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761036s004lbl.pdf

 

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