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

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

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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.



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