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Byetta

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Byetta

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. BYETTA (exenatide injection) 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 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.

BYETTA (exenatide injection) 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 (exenatide injection) has acute effects on pancreatic beta-cell responsiveness to glucose leading to insulin release predominantly in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. However, BYETTA (exenatide injection) does not impair the normal glucagon response to hypoglycemia.

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 (exenatide injection) 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 (exenatide injection) compared with saline (p < 0.001 for both).

Figure 1: Mean (+SEM) Insulin Secretion Rate During Infusion of BYETTA (exenatide injection) or Saline in Patients With Type 2 Diabetes and During Infusion of Saline in Healthy Subjects

Mean (+SEM) Insulin Secretion Rate During Infusion - Illustration

Glucagon secretion: In patients with type 2 diabetes, BYETTA (exenatide injection) 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.

Gastric emptying: BYETTA (exenatide injection) 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.

Pharmacodynamics

Postprandial Glucose

In patients with type 2 diabetes, BYETTA (exenatide injection) reduces postprandial plasma glucose concentrations (Figure 2).

Figure 2: Mean (+SEM) Postprandial Plasma Glucose Concentrations on Day 1 of BYETTA (exenatide injection) a Treatment in Patients With Type 2 Diabetes Treated With Metformin, a Sulfonylurea, or Both (N = 54)

Mean (+SEM) Postprandial Plasma Glucose Concentrations on Day 1 - Illustration

Fasting Glucose

In a single-dose crossover study in patients with type 2 diabetes and fasting hyperglycemia, immediate insulin release followed injection of BYETTA (exenatide injection) . Plasma glucose concentrations were significantly reduced with BYETTA (exenatide injection) compared with placebo (Figure 3).

Figure 3: Mean (+SEM) Serum Insulin and Plasma Glucose Concentrations Following a One-Time Injection of BYETTA (exenatide injection) a or Placebo in Fasting Patients With Type 2 Diabetes (N = 12)

Mean (+SEM) Serum Insulin and Plasma Glucose Concentrations - Illustration

Pharmacokinetics

Absorption

Following SC administration to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in 2.1 h. The mean peak exenatide concentration (Cmax) was 211 pg/mL and overall mean area under the time-concentration 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 (exenatide injection) in the abdomen, thigh, or upper arm.

Distribution

The mean apparent volume of distribution of exenatide following SC administration of a single dose of BYETTA (exenatide injection) 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.

Drug Interactions

Acetaminophen

When 1000 mg acetaminophen elixir was given with 10 mcg BYETTA (exenatide injection) (0 h) and 1 hour, 2 hours, and 4 hours after BYETTA (exenatide injection) 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 hour in the control period to 0.9 hour, 4.2 hours, 3.3 hours, and 1.6 hours, respectively. Acetaminophen AUC, Cmax and Tmax were not significantly changed when acetaminophen was given 1 hour before BYETTA (exenatide injection) injection.

Digoxin

Administration of repeated doses of BYETTA (exenatide injection) (10 mcg BID) 30 minutes before oral digoxin (0.25 mg QD) 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 (exenatide injection) (10 mcg BID) 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 (exenatide injection) , the use of BYETTA (exenatide injection) 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 (exenatide injection) (10 mcg BID) 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 (exenatide injection) (10 mcg BID) 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 (exenatide injection) 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 (exenatide injection) 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 (exenatide injection) 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 (exenatide injection) administration injection as compared to when the OC was given alone. The effect of BYETTA (exenatide injection) on OC pharmacokinetics is confounded by the possible food effect on OC in this study. Therefore, OC products should be administered at least one hour prior to BYETTA (exenatide injection) injection.

Warfarin

Administration of warfarin (25 mg) 35 minutes after repeated doses of BYETTA (exenatide injection) (5 mcg BID on days 1-2 and 10 mcg BID 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 (exenatide injection) did not significantly alter the pharmacodynamic properties (e.g., international normalized ratio) of warfarin [see DRUG INTERACTIONS].

Specific Populations

Renal Impairment

Pharmacokinetics of exenatide was studied in subjects with normal, mild, or moderate renal impairment and subjects with end stage renal disease. In subjects with mild to moderate renal impairment (creatinine clearance 30 to 80 mL/min), exenatide exposure was similar to that of subjects with normal renal function. However, in subjects with end-stage renal disease receiving dialysis, mean exenatide exposure increased by 3.37-fold compared to that of subjects with normal renal function. [see Use In Specific Populations].

Hepatic Impairment

No pharmacokinetic study has been performed in patients with a diagnosis of 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 of male and female patients suggests that gender does not influence the distribution and elimination of exenatide.

Race

Population pharmacokinetic analysis of samples from Caucasian, Hispanic, Asian, and Black patients suggests that race has no significant influence on the pharmacokinetics of exenatide.

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.

Clinical Studies

BYETTA (exenatide injection) 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.

Monotherapy

In a randomized, double-blind, placebo-controlled trial of 24 weeks duration, BYETTA (exenatide injection) 5 mcg BID (n = 77), BYETTA (exenatide injection) 10 mcg BID (n = 78), or placebo BID (n = 77) was used as monotherapy in patients with entry HbA1c ranging from 6.5-10%. All patients assigned to BYETTA (exenatide injection) initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive BYETTA (exenatide injection) 5 mcg BID or had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the trial. BYETTA (exenatide injection) or placebo was injected subcutaneously before the morning and evening meals. The majority of patients (68%) were Caucasian, 26% were West Asian, 3% were Hispanic, 3% were Black, and 0.4% were East Asian.

The primary endpoint was the change in HbA1c from baseline to Week 24 (or the last value at time of early discontinuation). Compared to placebo, BYETTA (exenatide injection) 5 mcg BID and 10 mcg BID resulted in statistically significant reductions in HbA1c from baseline at Week 24 (Table 5).

Table 5: Results of 24-Week Placebo-Controlled Trial of BYETTA (exenatide injection) Used as Monotherapy

  Placebo BID BYETTA 5 mcg BID BYETTA 10 mcg* BID
Intent-to-Treat Population (N) 77 77 78
HbA1c (%), Mean
  Baseline 7.8 7.9 7.8
  Change at Week 24† -0.2 -0.7 -0.9
  Difference from placebo†(95% CI)   -0.5 [-0.9, -0.2]‡ -0.7 [-1.0, -0.3]‡
Proportion Achieving HbA1c < 7% 38% 48% 53%
Body Weight (kg), Mean
  Baseline 86.1 85.1 86.2
  Change at Week 24† -1.5 -2.7 -2.9
  Difference from placebo†(95% CI)   -1.3 [-2.3, -0.2] -1.5 [-2.5, -0.4]
Fasting Serum Glucose§ (mg/dL), Mean
  Baseline 159 166 155
  Change at Week 24† -5 -17 -19
  Difference from placebo† (95% CI)   -12 [-23.2, -1.3] -14 [-24.5, -2.5]
* BYETTA (exenatide injection) 5 mcg twice daily (BID) for 1 month followed by 10 mcg BID for 5 months before the morning and evening meals.
† Least squares means are adjusted for screening HbA1c strata and baseline value of the dependent variable.
‡ p < 0.01, treatment vs. placebo.
§ Measured using the hexokinase-based glucose method.
BID = twice daily.

On average, there were no adverse effects of exenatide on blood pressure or lipids.

Combination Therapy

Three 30-week, double-blind, placebo-controlled trials were conducted to evaluate the safety and efficacy of BYETTA (exenatide injection) in patients with type 2 diabetes whose glycemic control was inadequate with metformin alone, a sulfonylurea alone, or metformin in combination with a sulfonylurea. In addition, a 16-week, placebo-controlled trial was conducted where BYETTA (exenatide injection) was added to existing thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without metformin, in patients with type 2 diabetes with inadequate glycemic control.

In the 30-week trials, after a 4-week placebo lead-in period, patients were randomly assigned to receive BYETTA (exenatide injection) 5 mcg BID, BYETTA (exenatide injection) 10 mcg BID, or placebo BID before the morning and evening meals, in addition to their existing oral antidiabetic agent. All patients assigned to BYETTA (exenatide injection) initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive BYETTA (exenatide injection) 5 mcg BID or had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the study. A total of 1446 patients were randomized in the three 30-week trials: 991 (69%) were Caucasian, 224 (16%) were Hispanic, and 174 (12%) were Black. Mean HbA1c values at baseline for the trials ranged from 8.2% to 8.7%.

In the placebo-controlled trial of 16 weeks duration, BYETTA (exenatide injection) (n = 121) or placebo (n = 112) was added to existing thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without metformin. Randomization to BYETTA (exenatide injection) or placebo was stratified based on whether the patients were receiving metformin. BYETTA (exenatide injection) treatment was initiated at a dose of 5 mcg BID for 4 weeks then increased to 10 mcg BID for 12 more weeks. Patients assigned to placebo received placebo BID throughout the study. BYETTA (exenatide injection) or placebo was injected subcutaneously before the morning and evening meals. In this trial, 79% of patients were taking a thiazolidinedione and metformin and 21% were taking a thiazolidinedione alone. The majority of patients (84%) were Caucasian, 8% were Hispanic and 3% were Black. The mean baseline HbA1c values were 7.9% for BYETTA (exenatide injection) and placebo.

The primary endpoint in each study was the mean change in HbA1c from baseline to study end (or early discontinuation). Table 6 summarizes the study results for the 30-week and 16-week clinical trials.

Table 6: Results of 30-Week and 16-Week Placebo-Controlled Trials of BYETTA (exenatide injection) Used in Combination with Oral Antidiabetic Agents

  Placebo BID BYETTA 5 mcg BID BYETTA 10 mcg* BID
In Combination With Metformin (30 Weeks)
Intent-to-Treat Population (N) 113 110 113
HbA1c (%), Mean
  Baseline 8.2 8.3 8.2
  Change at Week 30† -0.0 -0.5 -0.9
  Difference from placebo† (95% CI)   -0.5 [-0.7, -0.2]‡ -0.9 [-1.1, -0.6]‡
Proportion Achieving HbA 1c <7% 12% 32% 40%
Body Weight (kg), Mean
  Baseline 99.9 100.0 100.9
  Change at Week 30† -0.2 -1.3 -2.6
  Difference from placebo† (95% CI)   -1.1 [-2.2, -0.0] -2.4 [-3.5, -1.3]
Fasting Plasma Glucose§ (mg/dL), Mean
  Baseline 169 176 168
  Change at Week 30† +14 -5 -10
  Difference from placebo† (95% CI)   -20 [-32, -7] -24 [-37, -12]
Intent-to-Treat Population (N) 123 125 129
HbA1c (%), Mean
  Baseline 8.7 8.5 8.6
  Change at Week 30† +0.1 -0.5 -0.9
  Difference from placebo† (95% CI)   -0.6 [-0.9, -0.3]‡ -1.0 [-1.3, -0.7]‡
Proportion Achieving HbA 1c <7% 10% 25% 36%
Body Weight (kg), Mean
  Baseline 99.1 94.9 95.2
  Change at Week 30† -0.8 -1.1 -1.6
  Difference from placebo† (95% CI)   -0.3 [-1.1, 0.6] -0.9 [-1.7, -0.0]
Fasting Plasma Glucose§ (mg/dL), Mean
  Baseline 194 180 178
  Change at Week 30† +6 -5 -11
  Difference from placebo† (95% CI)   -11 [-25, 3] -17 [-30, -3]
Intent-to-Treat Population (N) 247 245 241
HbA1c (%), Mean
  Baseline 8.5 8.5 8.5
  Change at Week 30† +0.1 -0.7 -0.9
  Difference from placebo† (95% CI)   -0.8 [-1.0, -0.6] -1.0 [-1.2, -0.8]
Proportion Achieving HbA 1c <7% 8% 25% 31%
Body Weight (kg), Mean
  Baseline 99.1 96.9 98.4
  Change at Week 30† -0.9 -1.6 -1.6
  Difference from placebo† (95% CI)   -0.7 [-1.2, -0.2] -0.7 [-1.3, -0.2]
Fasting Plasma Glucose§ (mg/dL), Mean
  Baseline 181 182 178
  Change at Week 30† +13 -11 -12
  Difference from placebo† (95% CI)   -24 [-33, -15] -25 [-34, -16]
Intent-to-Treat Population (N) 112 Dose not studied 121
HbA1c (%), Mean
  Baseline 7.9 Dose not studied 7.9
  Change at Week 16† +0.1 Dose not studied -0.7
  Difference from placebo† (95% CI)   Dose not studied -0.9 [-1.1, -0.7]
Proportion Achieving HbA 1c <7% 15% Dose not studied 51%
Body Weight (kg), Mean
  Baseline 96.8 Dose not studied 97.5
  Change at Week 16† -0.0 Dose not studied -1.5
  Difference from placebo† (95% CI)   Dose not studied -1.5 [-2.2, -0.7]
Fasting Serum Glucose§ (mg/dL), Mean
  Baseline 159 Dose not studied 164
  Change at Week 16† +4 Dose not studied -21
  Difference from placebo† (95% CI)   Dose not studied -25 [-33, -16]
* BYETTA (exenatide injection) 5 mcg twice daily for 1 month followed by 10 mcg BID for 6 months for the 30-week trials or 10 mcg BID for 3 months in the 16-week trial before the morning and evening meals.
† Least squares means are adjusted for baseline HbA1c strata or value, investigator site, baseline value of the dependent variable (if applicable), and background antihyperglycemic therapy (if applicable).
p < 0.01, treatment vs. placebo.
Measured using the hexokinase-based glucose method.
BID = twice daily.

HbA1c

The addition of BYETTA (exenatide injection) to a regimen of metformin, a sulfonylurea, or both, resulted in statistically significant reductions from baseline in HbA1c compared with patients receiving placebo added to these agents in the three controlled trials (Table 6).

In the 16-week trial of BYETTA (exenatide injection) add-on to thiazolidinediones, with or without metformin, BYETTA (exenatide injection) resulted in statistically significant reductions from baseline in HbA1c compared with patients receiving placebo (Table 6).

Postprandial Glucose

Postprandial glucose was measured after a mixed meal tolerance test in 9.5% of patients participating in the 30-week add-on to metformin, add-on to sulfonylurea, and add-on to metformin in combination with sulfonylurea clinical trials. In this pooled subset of patients, BYETTA (exenatide injection) reduced postprandial plasma glucose concentrations in a dose-dependent manner. The mean (SD) change in 2-h postprandial glucose concentration following administration of BYETTA (exenatide injection) at Week 30 relative to baseline was -63 (65) mg/dL for 5 mcg BID (n=42), -71 (73) mg/dL for 10 mcg BID (n=52), and +11 (69) mg/dL for placebo BID (n=44).

Last reviewed on RxList: 6/20/2012
This monograph has been modified to include the generic and brand name in many instances.

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