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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.
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: Mean (SE) Insulin Secretion Rates During
Infusion of Exenatide or Placebo by Treatment, Time, and Glycemic Condition in
SE = standard error.
Notes: 5 mmol = 90 mg/dL, 4 mmol/L = 72 mg/dL, 3.2 mmol/L = 58 mg/dL; Study medication infusion was started at time = 0 minutes.
Statistical assessments were for the last 30 minutes of each glycemic step, during which the target glucose concentrations were maintained.
* p < 0.05, exenatide treatment relative to placebo.
Exenatide slows gastric emptying, thereby reducing the rate at which postprandial glucose appears in the circulation.
Infusion of exenatide in 8 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 2 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 280-310 pg/mL), the LS mean change from baseline was significantly greater with BYETTA (-126 mg/dL) than exenatide extended-release (-96 mg/dL).
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.
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 to 7, respectively, representing the hydration and erosion of the microspheres.
Following initiation of once every 7 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 7 days (weekly) dosing intervals indicating that steady state was achieved.
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/hour 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.
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.
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.
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.
In patients with mild to moderate hypertension stabilized on lisinopril (5-20 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-hour mean systolic and diastolic blood pressure.
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].
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].
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].
BYDUREON has not been studied in patients with acute or chronic hepatic impairment [see Use In Specific Populations].
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 Populations].
Population pharmacokinetic analysis suggests that gender does not influence the steady-state concentrations of exenatide following BYDUREON administration.
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.
BYDUREON has not been studied in pediatric patients [see Use in Specific Populations].
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 to 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.
BYDUREON has been studied as monotherapy and in combination with metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, or a combination of metformin and a thiazolidinedione.
24-Week Comparator-Controlled Study
A 24-week, randomized, open-label trial was conducted to compare the safety and efficacy of BYDUREON to BYETTA in patients with type 2 diabetes and inadequate glycemic control with diet and exercise alone or with oral antidiabetic therapy, including metformin, a sulfonylurea, a thiazolidinedione, or combination of two of those therapies.
A total of 252 patients were studied: 149 (59%) were Caucasian, 78 (31%) Hispanic, 15 (6%) Black, and 10 (4%) Asian. Patients were treated with diet and exercise alone (19%), a single oral antidiabetic agent (47%), or combination therapy of oral antidiabetic agents (35%). The mean baseline HbA1c was 8.4%. Patients were randomly assigned to receive BYDUREON 2 mg once every 7 days (weekly) or BYETTA (10 mcg twice daily), in addition to existing oral antidiabetic agents. Patients assigned to BYETTA initiated treatment with 5 mcg twice daily then increased the dose to 10 mcg twice daily after 4 weeks.
The primary endpoint was change in HbA1c from baseline to Week 24 (or the last value at time of early discontinuation). Change in body weight was a secondary endpoint. Twenty-four week study results are summarized in Table 4.
Table 4: Results of 24-Week Trial of BYDUREON
|BYDUREON 2 mg||BYETTA 10 mcg*|
|Intent-to-Treat Population (N)||129||123|
|Mean Change at Week 24†||-1.6||-0.9|
|Difference from BYETTA† [95% CI]||-0.7 [-0.9, -0.4] ¶|
|Percentage Achieving HbA1c < 7% at Week 24 (%)||58¶||30|
|Fasting Plasma Glucose (mg/dL)|
|Mean Change at Week 24||-25||-5|
|Difference from BYETTA† [95% CI]||-20 [-31, -10] ¶|
|N = number of patients in each
Note: mean change is least squares mean change.
* BYETTA 5 mcg twice daily before the morning and evening meals for 4 weeks followed by 10 mcg twice daily for 20 weeks.
† Least squares (LS) means are adjusted for baseline HbA1c strata, background antihyperglycemic therapy, and baseline value of the dependent variable (if applicable).
¶ p < 0.001, treatment vs comparator.
Reductions from mean baseline (97/94 kg) in body weight were observed in both BYDUREON (-2.3 kg) and BYETTA (-1.4 kg) treatment groups.
BYDUREON did not have adverse effects on blood pressure. An LS mean increase from baseline (74 beats per minute) in heart rate of 4 beats per minute was observed with BYDUREON treatment and 2 beats per minute with BYETTA treatment. The long-term effects of the increase in pulse rate have not been established [see WARNINGS AND PRECAUTIONS].
Last reviewed on RxList: 6/9/2014
This monograph has been modified to include the generic and brand name in many instances.
Additional Bydureon Information
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