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Byetta (Exenatide Injection) - Description and Clinical Pharmacology

 
 



DESCRIPTION

BYETTA® (exenatide) is a synthetic peptide that has incretin-mimetic actions and was originally identified in the lizard Heloderma suspectum. BYETTA enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying. Exenatide differs in chemical structure and pharmacological action from insulin, sulfonylureas (including D-phenylalanine derivatives and meglitinides), biguanides, thiazolidinediones, and alpha-glucosidase inhibitors.

Exenatide is a 39−amino acid peptide amide. Exenatide has the empirical formula C184H282N50O60S and 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

BYETTA is supplied for subcutaneous (SC) injection as a sterile, preserved isotonic solution in a glass cartridge that has been assembled in a pen-injector (pen). Each milliliter (mL) contains 250 micrograms (mcg) synthetic exenatide, 2.2 mg metacresol as an antimicrobial preservative, mannitol as a tonicity-adjusting agent, and glacial acetic acid and sodium acetate trihydrate in water for injection as a buffering solution at pH 4.5. Two prefilled pens are available to deliver unit doses of 5 mcg or 10 mcg. Each prefilled pen will deliver 60 doses to provide 30 days of twice daily administration (BID).

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. 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

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.

Pharmacokinetics

Absorption

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.

Distribution

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.

Special Populations

Renal Insufficiency

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).

Hepatic Insufficiency

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).

Geriatric

Population pharmacokinetic analysis of patients (range from 22 to 73 years) suggests that age does not influence the pharmacokinetic properties of exenatide.

Pediatric

Exenatide has not been studied in pediatric patients.

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 patients including Caucasian, Hispanic, and Black, suggests that race has no significant influence on the pharmacokinetics of exenatide.

Obesity

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.

Drug Interactions

Digoxin

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

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.

Lisinopril

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.

Acetaminophen

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.

Warfarin

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.

Pharmacodynamics

Postprandial Glucose

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 BYETTA<sup>a</sup> Treatment in Patients With Type 2 Diabetes Treated With Metformin, a Sulfonylurea, or Both (N = 54)

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)

Fasting Glucose

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 BYETTA<sup>a</sup> or Placebo in Fasting Patients With Type 2 Diabetes (N = 12)

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)

CLINICAL STUDIES

Use with metformin and/or a sulfonylurea

Three 30-week, double-blind, placebo-controlled trials were conducted to evaluate the safety and efficacy of BYETTA in patients with type 2 diabetes whose glycemic control was inadequate with metformin alone, a sulfonylurea alone, or metformin in combination with a sulfonylurea.

A total of 1446 patients were randomized in these three trials: 991 (68.5%) were Caucasian, 224 (15.5%) were Hispanic, and 174 (12.0%) were Black. Mean HbA1c values at baseline for the trials ranged from 8.2% to 8.7%. After a 4-week placebo lead-in period, patients were randomly assigned to receive BYETTA 5 mcg BID, BYETTA 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 began a treatment initiation period with 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive BYETTA 5 mcg BID or had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the study.

The primary endpoint in each study was mean change from baseline HbA1c at 30 weeks. Thirty-week study results are summarized in Table 1.

Table 1: Results of Thirty-Week Placebo-Controlled Trials of BYETTA in Patients With Inadequate Glucose Control Despite the Use of Metformin, a Sulfonylurea, or Both
Placebo
BID
BYETTA
5 mcg BID
BYETTA
10 mcg 1 BID
In Combination With Metformin
Intent-to-Treat Population (N)113110113
HbA1c (%), Mean
  Baseline8.28.38.2
  Change at Week 30+0.1−0.4 2 −0.8 3
Proportion Achieving HbA1c≤7% 4 13.0%31.6%46.4%
Body Weight (kg), Mean
  Baseline99.9100.0100.9
  Change at Week 30−0.3−1.6−2.8
In Combination With a Sulfonylurea
Intent-to-Treat Population (N)123125129
HbA1c (%), Mean
  Baseline8.78.58.6
  Change at Week 30+0.1−0.5−0.9
Proportion Achieving HbA1c≤7%8.8%32.6%41.3%
Body Weight (kg), Mean
  Baseline99.194.995.2
  Change at Week 30−0.6−0.9−1.6
In Combination With Metformin and a Sulfonylurea
Intent-to-Treat Population (N)247245241
HbA1c (%), Mean
  Baseline8.58.58.5
  Change at Week 30+0.2−0.6−0.8
Proportion Achieving HbA1c≤7%9.2%27.4%33.5%
Body Weight (kg), Mean
  Baseline99.196.998.4
  Change at Week 30−0.9−1.6−1.6

1 BYETTA 5 mcg twice daily (BID) for 1 month followed by 10 mcg BID for 6 months before the morning and evening meals.
2 p ≤0.05, treatment vs. placebo
3 p ≤0.0001, treatment vs. placebo
4 Patients eligible for the analysis with baseline HbA1c>7%.

HbA1c

The addition of BYETTA to a regimen of metformin, a sulfonylurea, or both, resulted in statistically significant reductions from baseline HbA1c at Week 30 compared with patients receiving placebo added to these agents in the three controlled trials (Table 1). In addition, a statistically significant dose-effect was observed between 5-mcg and 10-mcg BYETTA groups for the change from baseline HbA1c at Week 30 in the three studies.

Fasting and Postprandial Glucose

Long-term use of BYETTA in combination with metformin, a sulfonylurea, or both, reduced both fasting and postprandial plasma glucose concentrations in a statistically significant, dose-dependent manner through Week 30. A statistically significant reduction from baseline in both mean fasting and postprandial glucose concentrations was observed at Week 30 in both BYETTA groups compared with placebo in data combined from the three controlled trials. The change in fasting glucose concentration at Week 30 compared with baseline was −8 mg/dL for BYETTA 5 mcg BID and −10 mg/dL for BYETTA 10 mcg BID, compared with +12 mg/dL for placebo. The change in 2-h postprandial glucose concentration following administration of BYETTA at Week 30 compared with baseline was −63 mg/dL for 5 mcg BID and −71 mg/dL for 10 mcg BID, compared with +11 mg/dL for placebo.

Proportion of Patients Achieving HbA1c≤7%

BYETTA in combination with metformin, a sulfonylurea, or both, resulted in a greater, statistically significant proportion of patients achieving an HbA1c≤7% at Week 30 compared with patients receiving placebo in combination with these agents (Table 1).

Body Weight

In the three controlled trials, a decrease from baseline body weight at Week 30 was associated with BYETTA 10 mcg BID compared with placebo BID in patients with type 2 diabetes (Table 1).

One-Year Clinical Results

The cohort of 163 patients from the 30-week placebo-controlled trials who completed a total of 52 weeks of treatment with BYETTA 10 mcg BID had HbA1c changes from baseline of −1.0% and −1.1% at 30 and 52 weeks of treatment, respectively, with accompanying changes from baseline in fasting plasma glucose of −14.0 mg/dL and −25.3 mg/dL, and body weight changes of −2.6 kg and −3.6 kg. This cohort had baseline values similar to those of the entire controlled-trial population.

Use with a thiazolidinedione

In a randomized, double-blind, placebo-controlled trial of 16 weeks duration, BYETTA (n=121) or placebo (n=112) was added to existing thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without metformin, in patients with type 2 diabetes with inadequate glycemic control. Randomization to BYETTA or placebo was stratified based on whether the patients were receiving metformin. Patients assigned to placebo received placebo BID throughout the study. BYETTA or placebo was injected subcutaneously before the morning and evening meals. Seventy-nine percent 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 similar for BYETTA and placebo (7.9%). BYETTA treatment was initiated at a dose of 5 mcg BID for 4 weeks then increased to 10 mcg BID for 12 more weeks.

Sixteen-week study results are summarized in Table 2. Compared to placebo, BYETTA resulted in statistically significant reductions in HbA1c from baseline at Week 16. Treatment effects for HbA1c were similar in the two sub-groups defined by underlying treatment stratum (thiazolidinediones alone versus thiazolidinediones plus metformin). The change in fasting serum glucose concentration from baseline to Week 16 was statistically significant compared with placebo (−21 mg/dL for BYETTA 10 mcg BID compared with +4 mg/dL for placebo).

Table 2: Results of 16-Week Placebo-Controlled Trial of BYETTA in Patients With Inadequate Glucose Control Despite the Use of a Thiazolidinedione (TZD) or a Thiazolidinedione plus Metformin
Placebo
BID
BYETTA
10 mcg 1 BID
In Combination With a TZD or a TZD plus MET
Intent-to-Treat Population (N)112121
HbA1c (%), Mean
  Baseline7.97.9
  Change at Week 16+0.1−0.8 2
Proportion Achieving HbA1c≤7% 3 16.2%62.3%
Body Weight (kg), Mean
  Baseline96.997.5
  Change at Week 16−0.2−1.5

1 BYETTA 5 mcg twice daily (BID) for 1 month followed by 10 mcg BID for 3 months before the morning and evening meals.
2 p <0.0001, treatment vs. placebo
3 Patients eligible for the analysis with baseline HbA1c>7%.

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