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. Exenatide is an incretin mimetic agent that mimics the enhancement of glucose-dependent insulin secretion and several other antihyperglycemic actions of incretins.
The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind and activate the known 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 beta cells in the presence of elevated glucose concentrations. When administered in vivo, exenatide mimics certain antihyperglycemic actions of GLP-1.
BYETTA 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: BYETTA has acute effects on pancreatic beta-cell responsiveness to glucose and leads to insulin release only in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia.
First-phase insulin response: In healthy individuals, robust insulin secretion occurs during the first 10 minutes following intravenous (IV) glucose administration. This secretion, known as the "first-phase insulin response," is characteristically absent in patients with type 2 diabetes. The loss of the first-phase insulin response is an early beta-cell defect in type 2 diabetes. Administration of BYETTA at therapeutic plasma concentrations restored first-phase insulin response to an IV bolus of glucose in patients with type 2 diabetes (Figure 1). Both first-phase insulin secretion and second-phase insulin secretion were significantly increased in patients with type 2 diabetes treated with BYETTA compared with saline (p <0.001 for both).
Figure 1: Mean (+SEM) Insulin Secretion Rate During Infusion of BYETTA or Saline in Patients With Type 2 Diabetes and During Infusion of Saline in Healthy Subjects
Glucagon secretion: In patients with type 2 diabetes, BYETTA moderates glucagon secretion and lowers serum glucagon concentrations during periods of hyperglycemia. Lower glucagon concentrations lead to decreased hepatic glucose output and decreased insulin demand. However, BYETTA does not impair the normal glucagon response to hypoglycemia.
Gastric emptying: BYETTA slows gastric emptying, thereby reducing the rate at which meal-derived glucose appears in the circulation.
Food intake: In both animals and humans, administration of exenatide has been shown to reduce food intake.
Following SC administration to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in 2.1 h. Mean peak exenatide concentration (Cmax) was 211 pg/mL and overall mean area under the curve (AUC0-inf) was 1036 pg•h/mL following SC administration of a 10 mcg dose of BYETTA. Exenatide exposure (AUC) increased proportionally over the therapeutic dose range of 5 mcg to 10 mcg. The Cmax values increased less than proportionally over the same range. Similar exposure is achieved with SC administration of BYETTA in the abdomen, thigh, or arm.
The mean apparent volume of distribution of exenatide following SC administration of a single dose of BYETTA is 28.3 L.
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 the mean terminal half-life is 2.4 h. These pharmacokinetic characteristics of exenatide are independent of the dose. In most individuals, exenatide concentrations are measurable for approximately 10 h post-dose.
In patients with mild to moderate renal impairment (creatinine clearance 30 to 80 mL/min), exenatide clearance was only mildly reduced; therefore, no dosage adjustment of BYETTA is required in patients with mild to moderate renal impairment. However, in patients with end-stage renal disease receiving dialysis, mean exenatide clearance is reduced to 0.9 L/h compared with 9.1 L/h in healthy subjects (see PRECAUTIONS, General).
No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic insufficiency. Because exenatide is cleared primarily by the kidney, hepatic dysfunction is not expected to affect blood concentrations of exenatide (see Pharmacokinetics, Metabolism and Elimination).
Population pharmacokinetic analysis of patients (range from 22 to 73 years) suggests that age does not influence the pharmacokinetic properties of exenatide.
Exenatide has not been studied in pediatric patients.
Population pharmacokinetic analysis of male and female patients suggests that gender does not influence the distribution and elimination of exenatide.
Population pharmacokinetic analysis of patients including Caucasian, Hispanic, and Black, suggests that race has no significant influence on the pharmacokinetics of exenatide.
Population pharmacokinetic analysis of obese (BMI ≥30 kg/m2) and non-obese patients suggests that obesity has no significant effect on the pharmacokinetics of exenatide.
Coadministration of repeated doses of BYETTA (10 mcg BID) decreased the Cmax of oral digoxin (0.25 mg QD) by 17% and delayed the Tmax by approximately 2.5 h; however, the overall steady-state pharmacokinetic exposure (AUC) was not changed.
Lovastatin AUC and Cmax were decreased approximately 40% and 28%, respectively, and Tmax was delayed about 4 h when BYETTA (10 mcg BID) was administered concomitantly with a single dose of lovastatin (40 mg) 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 to 20 mg/day), BYETTA (10 mcg BID) did not alter steady-state Cmax or AUC of lisinopril. Lisinopril steady-state Tmax was delayed by 2 h. There were no changes in 24-h mean systolic and diastolic blood pressure.
When 1000 mg acetaminophen elixir was given with 10 mcg BYETTA (0 h) and 1 h, 2 h, and 4 h after BYETTA injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively; Tmax was increased from 0.6 h in the control period to 0.9 h, 4.2 h, 3.3 h, and 1.6 h, respectively. Acetaminophen AUC, Cmax and Tmax were not significantly changed when acetaminophen was given 1 h before BYETTA injection.
Coadministration of repeat doses of BYETTA (5 mcg BID on days 1-2 and 10 mcg BID on days 3-9) in healthy volunteers, delayed warfarin (25 mg) Tmax by about 2 h. No clinically relevant effects on Cmax or AUC of S- and R-enantiomers of warfarin were observed. BYETTA did not change the pharmacodynamic properties (as assessed by INR response) of warfarin.
In patients with type 2 diabetes, BYETTA reduces the postprandial plasma glucose concentrations (Figure 2).
Figure 2: Mean (+SEM) Postprandial Plasma Glucose Concentrations on Day 1 of BYETTAa Treatment in Patients With Type 2 Diabetes Treated With Metformin, a Sulfonylurea, or Both (N = 54)
In a single-dose crossover study in patients with type 2 diabetes and fasting hyperglycemia, an immediate insulin release followed injection of BYETTA. Plasma glucose concentrations were significantly reduced with BYETTA compared with placebo (Figure 3).
Figure 3: Mean (+SEM) Serum Insulin and Plasma Glucose Concentrations Following a One-Time Injection of BYETTAa or Placebo in Fasting Patients With Type 2 Diabetes (N = 12)