BYDUREON (Page 4 of 6)

11 DESCRIPTION

BYDUREON (exenatide extended-release for injectable suspension) is supplied as a sterile powder to be suspended in the diluent included in the single-dose tray and administered by subcutaneous injection. Exenatide is a 39-amino acid synthetic peptide amide with an empirical formula of C184 H282 N50 O60 S and a molecular weight of 4186.6 Daltons. The amino acid sequence for exenatide is shown below.

H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2

BYDUREON is a white to off-white powder that is available in a dosage strength of 2 mg exenatide per vial. Exenatide is incorporated in an extended release microsphere formulation containing the 50:50 poly(D,L-lactide-co-glycolide) polymer (37.2 mg per vial) along with sucrose (0.8 mg per vial). The powder must be suspended in the diluent prior to injection. The diluent is provided in a prefilled syringe. Each prefilled syringe delivers 0.65 mL of the diluent as a clear, colorless to pale yellow solution composed of carboxymethylcellulose sodium (23 mg), polysorbate 20 (0.77 mg), sodium phosphate monobasic monohydrate (0.74 mg), sodium phosphate dibasic heptahydrate (0.62 mg), sodium chloride (5.0 mg), and water for injection.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions following their release into the circulation from the gut. BYDUREON is a GLP-1 receptor agonist that enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying.

The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide is a GLP-1 receptor agonist that has been shown to bind and activate the human GLP-1 receptor in vitro. This leads to an increase in both glucose-dependent synthesis of insulin and in vivo secretion of insulin from pancreatic beta cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways. Exenatide promotes insulin release from pancreatic beta cells in the presence of elevated glucose concentrations.

12.2 Pharmacodynamics

Exenatide improves glycemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes through the actions described below.

Glucose-dependent insulin secretion: The effect of exenatide infusion on glucose-dependent insulin secretion rates (ISR) was investigated in 11 healthy subjects. In these healthy subjects, on average, the ISR response was glucose-dependent (Figure 1). Exenatide did not impair the normal glucagon response to hypoglycemia.

Figure 1
(click image for full-size original)

SE = standard error.
Notes: 5 mmol = 90mg/dL, 4 mmol/L = 72 mg/dL, 3.2 mmol/L = 58 mg/dL; Study medication infusion was started at time = 0 min.
Statistical assessments were for the last 30 min of each glycemic step, during which the target glucose concentrations were maintained.*p <0.05, exenatide treatment relative to placebo.

Figure 1: Mean (SE) Insulin Secretion Rates During Infusion of Exenatide or Placebo by Treatment, Time, and Glycemic Condition in Healthy Subjects

Glucagon secretion: In patients with type 2 diabetes, exenatide moderates glucagon secretion and lowers serum glucagon concentrations during periods of hyperglycemia.

Gastric emptying: Exenatide slows gastric emptying, thereby reducing the rate at which postprandial glucose appears in the circulation.

Food intake: Infusion of exenatide in eight healthy subjects resulted in a 19% decrease in caloric intake following an ad libitum meal.

Fasting and Postprandial Glucose

In a separate 15-week controlled study, where fasting glucose was assessed on a weekly basis, BYDUREON treatment resulted in a mean reduction in fasting glucose of 17 mg/dL following two weeks of therapy with full effect on fasting glucose not observed until approximately 9 weeks.

In a 30-week controlled study of exenatide extended-release compared to BYETTA, postprandial glucose levels were measured during a mixed meal tolerance test in a subset of patients with type 2 diabetes mellitus. Following treatment for 14 weeks, when steady-state concentrations had been achieved (approximately 280 to 310 pg/mL), the LS mean change from baseline was significantly greater with BYETTA (-126 mg/dL) than exenatide extended-release (-96 mg/dL).

Cardiac Electrophysiology

The effect of exenatide at therapeutic (253 pg/mL) and supratherapeutic (627 pg/mL) concentrations, following an intravenous infusion on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg) three-period crossover thorough QT study in 74 healthy subjects. The upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on population correction method (QTcP) was below 10 ms. Therefore, exenatide was not associated with prolongation of the QTc interval at therapeutic and supratherapeutic concentrations.

12.3 Pharmacokinetics

Absorption

Following a single dose of BYDUREON, exenatide is released from the microspheres over approximately 10 weeks. There is an initial period of release of surface-bound exenatide followed by a gradual release of exenatide from the microspheres, which results in two subsequent peaks of exenatide in plasma at around week 2 and week 6-7, respectively, representing the hydration and erosion of the microspheres.

Following initiation of once every seven days (weekly) administration of 2 mg BYDUREON, gradual increase in the plasma exenatide concentration is observed over 6 to 7 weeks. After 6 to 7 weeks, mean exenatide concentrations of approximately 300 pg/mL were maintained over once every seven days (weekly) dosing intervals indicating that steady-state was achieved.

Distribution

The mean apparent volume of distribution of exenatide following subcutaneous administration of a single dose of BYETTA is 28.3 L and is expected to remain unchanged for BYDUREON.

Metabolism and Elimination

Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. The mean apparent clearance of exenatide in humans is 9.1 L/h and is independent of the dose. Approximately 10 weeks after discontinuation of BYDUREON therapy, plasma exenatide concentrations generally fall below the minimal detectable concentration of 10 pg/mL.

Drug Interactions

Acetaminophen

When 1000 mg acetaminophen tablets were administered, either with or without a meal, following 14 weeks of BYDUREON therapy (2 mg weekly), no significant changes in acetaminophen AUC were observed compared to the control period. Acetaminophen Cmax decreased by 16% (fasting) and 5% (fed) and Tmax was increased from approximately 1 hour in the control period to 1.4 hours (fasting) and 1.3 hours (fed).

The following drug interactions have been studied using BYETTA. The potential for drug-drug interaction with BYDUREON is expected to be similar to that of BYETTA.

Digoxin

Administration of repeated doses of BYETTA 30 minutes before oral digoxin (0.25 mg once-daily) decreased the Cmax of digoxin by 17% and delayed the Tmax of digoxin by approximately 2.5 hours; however, the overall steady-state pharmacokinetic exposure (e.g. AUC) of digoxin was not changed.

Lovastatin

Administration of BYETTA (10 mcg twice daily) 30 minutes before a single oral dose of lovastatin (40 mg) decreased the AUC and Cmax of lovastatin by approximately 40% and 28%, respectively, and delayed the Tmax by about 4 hours compared with lovastatin administered alone. In the 30-week controlled clinical trials of BYETTA, the use of BYETTA in patients already receiving HMG CoA reductase inhibitors was not associated with consistent changes in lipid profiles compared to baseline.

Lisinopril

In patients with mild to moderate hypertension stabilized on lisinopril (5 to 20 mg/day), BYETTA (10 mcg twice daily) did not alter steady-state Cmax or AUC of lisinopril. Lisinopril steady-state Tmax was delayed by 2 hours. There were no changes in 24-h mean systolic and diastolic blood pressure.

Oral Contraceptives

The effect of BYETTA (10 mcg twice-daily) on single and on multiple doses of a combination oral contraceptive (30 mcg ethinyl estradiol plus 150 mcg levonorgestrel) was studied in healthy female subjects. Repeated daily doses of the oral contraceptive (OC) given 30 minutes after BYETTA administration decreased the Cmax of ethinyl estradiol and levonorgestrel by 45% and 27%, respectively and delayed the Tmax of ethinyl estradiol and levonorgestrel by 3.0 hours and 3.5 hours, respectively, as compared to the oral contraceptive administered alone. Administration of repeated daily doses of the OC one hour prior to BYETTA administration decreased the mean Cmax of ethinyl estradiol by 15% but the mean Cmax of levonorgestrel was not significantly changed as compared to when the OC was given alone. BYETTA did not alter the mean trough concentrations of levonorgestrel after repeated daily dosing of the oral contraceptive for both regimens. However, the mean trough concentration of ethinyl estradiol was increased by 20% when the OC was administered 30 minutes after BYETTA administration injection as compared to when the OC was given alone. The effect of BYETTA on OC pharmacokinetics is confounded by the possible food effect on OC in this study [see Drug Interactions (7.1)].

Warfarin

Administration of warfarin (25 mg) 35 minutes after repeated doses of BYETTA (5 mcg twice-daily on days 1-2 and 10 mcg twice-daily on days 3-9) in healthy volunteers delayed warfarin Tmax by approximately 2 hours. No clinically relevant effects on Cmax or AUC of S- and R-enantiomers of warfarin were observed. BYETTA did not significantly alter the pharmacodynamic properties (e.g., international normalized ratio) of warfarin [see Drug Interactions (7.2)].

Specific Populations

Renal Impairment

BYDUREON has not been studied in patients with severe renal impairment (creatinine clearance <30 mL/min) or end-stage renal disease receiving dialysis. Population pharmacokinetic analysis of renally-impaired patients receiving 2 mg BYDUREON indicate that there is a 62% and 33% increase in exposure in moderate (N=10) and mild (N=56) renally-impaired patients, respectively as compared to patients with normal renal function (N=84).

In a study of BYETTA in subjects with end-stage renal disease receiving dialysis, mean exenatide exposure increased by 3.4-fold compared to that of subjects with normal renal function [see Use in Specific Populations (8.6)].

Hepatic Impairment

BYDUREON has not been studied in patients with acute or chronic hepatic impairment [see Use in Specific Populations (8.7)].

Age

Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests that age does not influence the pharmacokinetic properties of exenatide [see Use in Specific Population (8.5)].

Gender

Population pharmacokinetic analysis suggests that gender does not influence the steady-state concentrations of exenatide following BYDUREON administration.

Race

There were no apparent differences in steady-state concentrations of exenatide among Caucasian, Hispanic, and Black patients following BYDUREON administration.

Body Mass Index

Population pharmacokinetic analysis of patients with body mass indices (BMI) ≥30 kg/m2 and <30 kg/m2 suggests that BMI has no significant effect on the pharmacokinetics of exenatide.

Pediatric

BYDUREON has not been studied in pediatric patients [see Use in Specific Populations (8.4)]

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