CLINICAL PHARMACOLOGY
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.
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.
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.
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
].
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
].
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
].
Hepatic Impairment
BYDUREON has not been studied in patients with acute or chronic hepatic impairment [see
Use in Specific Populations
].
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
].
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
]
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 104-week carcinogenicity study was conducted with exenatide extended-release in male and female rats at doses of 0.3, 1.0 and 3.0 mg/kg (2, 9, and 26-times human systemic exposure based on AUC, respectively) administered by subcutaneous injection every other week. A statistically significant increase in thyroid C-cell tumor incidence was observed in both males and females. The incidence of C-cell adenomas was statistically significantly increased at all doses (27% to 31%) in females and at 1.0 and 3.0 mg/kg (46% and 47%, respectively) in males compared with the control group (13% for males and 7% for females). A statistically significantly higher incidence of C-cell carcinomas occurred in the high dose group females (6%), while numerically higher incidences of 3%, 7%, and 4% (non-statistically significant versus controls) were noted in the low, mid, and high dose group males compared with the control group (0% for both males and females). An increase in benign fibromas was seen in the skin subcutis at injection sites of males given 3 mg/kg. No treatment-related injection site fibrosarcomas were observed at any dose. The human relevance of these findings is currently unknown.
A 104-week carcinogenicity study was conducted with exenatide, the active ingredient in BYDUREON, in male and female rats at doses of 18, 70, or 250 mcg/kg/day (3, 6, and 27 times human systemic exposure based on AUC, respectively) administered by once daily bolus subcutaneous injection. Benign thyroid C-cell adenomas were observed in female rats at all exenatide doses. The incidences in female rats were 8% and 5% in the two control groups and 14%, 11%, and 23% in the low, medium, and high dose groups.
In a 104-week carcinogenicity study with exenatide, the active ingredient in BYDUREON, in male and female mice at doses of 18, 70, or 250 mcg/kg/day administered by once daily bolus subcutaneous injection, no evidence of tumors was observed at doses up to 250 mcg/kg/day, a systemic exposure up to 16 times the human exposure resulting from the recommended dose of 2 mg/week, based on AUC. The carcinogenicity of exenatide extended-release has not been evaluated in mice.
BYDUREON and exenatide, the active ingredient in BYDUREON, were not mutagenic or clastogenic, with or without metabolic activation, in the Ames bacterial mutagenicity assay or chromosomal aberration assay in Chinese hamster ovary cells. Exenatide was negative in the in vivo mouse micronucleus assay.
In mouse fertility studies with exenatide, the active ingredient in BYDUREON, at twice-daily subcutaneous doses of 6, 68 or 760 mcg/kg/day, males were treated for 4 weeks prior to and throughout mating, and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 760 mcg/kg/day, a systemic exposure 148 times the human exposure resulting from the recommended dose of 2 mg/week, based on AUC.
Reproductive and Developmental Toxicology
A rat embryo-fetal developmental toxicity study was conducted with exenatide extended-release. A complete reproductive and developmental toxicity program was conducted with exenatide, the active ingredient in BYDUREON.
Fetuses from pregnant rats given subcutaneous doses of exenatide extended-release at 0.3, 1 or 3 mg/kg on gestation days 6, 9, 12 and 15 demonstrated reduced fetal growth at all doses and produced skeletal ossification deficits at 1 and 3 mg/kg in association with maternal effects (decreased food intake and decreased body weight gain). There was no evidence of malformations. Doses of 0.3, 1 and 3 mg/kg correspond to systemic exposures of 3, 7 and 17-times, respectively, the human exposure resulting from the recommended dose of 2 mg/week, based on AUC.
In female mice given twice-daily subcutaneous doses of 6, 68, or 760 mcg/kg/day exenatide, the active ingredient in BYDUREON, beginning 2 weeks prior to and throughout mating until gestation day 7, there were no adverse fetal effects at doses up to 760 mcg/kg/day, systemic exposures up to 148 times the human exposure resulting from the maximum recommended dose of 2 mg/day, based on AUC.
In pregnant mice given twice-daily subcutaneous doses of 6, 68, 460, or 760 mcg/kg/day exenatide, the active ingredient in BYDUREON, from gestation day 6 through 15 (organogenesis), cleft palate (some with holes) and irregular fetal skeletal ossification of rib and skull bones were observed at 6 mcg/kg/day, a systemic exposure equal to the human exposure resulting from the maximum recommended dose of 2 mg/day, based on AUC.
In pregnant rabbits given twice-daily subcutaneous doses of 0.2, 2, 22, 156, or 260 mcg/kg/day exenatide, the active ingredient in BYDUREON, from gestation day 6 through 18 (organogenesis), irregular fetal skeletal ossifications were observed at 2 mcg/kg/day, a systemic exposure 4 times the human exposure resulting from the maximum recommended dose of 2 mg/day, based on AUC.
In pregnant mice given twice-daily subcutaneous doses of 6, 68, or 760 mcg/kg/day exenatide, the active ingredient in BYDUREON, from gestation day 6 through lactation day 20 (weaning), an increased number of neonatal deaths was observed on postpartum days 2-4 in dams given 6 mcg/kg/day, a systemic exposure equal to the human exposure resulting from the maximum recommended dose of 2 mg/day, based on AUC.
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