Injection Of Exenatide Research Articles

Dose–response for glycaemic and metabolic changes 28 days after single injection of long-acting release exenatide in diabetic fatty Zucker rats

Exenatide (exendin-4) injected subcutaneously twice daily reduces glycaemic deterioration in diabetic fatty Zucker (ZDF) rats and reduces HbA1c in humans with type 2 diabetes. Because tachyphylaxis may develop with continuous peptide exposure, we examined the activity of a long-acting-release (LAR) formulation of exenatide on HbA1c, insulin sensitivity and beta cell secretion in ZDF rats. Single subcutaneous injections of a poly-lactide-glycolide microsphere suspension (3% peptide) containing 0, 1, 10, 100, 1,000, 3,000 or 9,000 mug exenatide were administered to 9-week-old ZDF rats with matched initial HbA1c values (n=7 rats/group). In contrast to the progressive 3.22+/-0.42% increase in HbA1c in control ZDF rats observed over 28 days, single exenatide-LAR injections dose-proportionally prevented such glycaemic deterioration (median effective dose 74 microg+/-0.1 log per rat; median effective concentration 52 pmol/l+/-0.06 log). Hyperinsulinaemic-euglycaemic clamp procedures incorporating an intraclamp glucose challenge performed 28 days after treatment revealed increases in beta cell response to the glucose challenge at lower exenatide-LAR doses, and up to a 2.1-fold increase in insulin sensitivity at higher exenatide-LAR doses. The finding that a single dose of exenatide-LAR enhanced glucose control for 28 days in the ZDF rat model of type 2 diabetes suggests that tachyphylaxis is unlikely to be a feature of exenatide-LAR preparations, and supports further clinical exploration.

Pharmacokinetics of an Oral Drug (Acetaminophen) Administered at Various Times in Relation to Subcutaneous Injection of Exenatide (Exendin‐4) in Healthy Subjects

Exenatide is an incretin mimetic with potential glucoregulatory activity in type 2 diabetes. This randomized, single-blind, placebo-controlled 6-way crossover study assessed exenatide's effect on acetaminophen pharmacokinetics. Of 40 randomized healthy subjects, 39 completed the study. On the placebo day, acetaminophen (1000 mg) was ingested and placebo injected subcutaneously at 0 hours. On exenatide days, acetaminophen was ingested at -1, 0, +1, +2, and +4 hours, relative to the 10 mug exenatide injected subcutaneously at 0 hours. With exenatide injection, mean plasma acetaminophen AUC(0-12 h) values were reduced by 11% to 24% (vs placebo). Peak plasma acetaminophen concentrations were similar for the -1-hour and placebo groups and reduced by 37% to 56% at other times. The most frequent adverse events were generally mild to moderate nausea and vomiting. Exenatide treatment concurrent with or preceding acetaminophen ingestion slowed acetaminophen absorption but had minimal effect on the extent of absorption.

Effect of injection site on relative bioavailability of exenatide (synthetic exendin-4)

Exenatide is an incretin mimetic with glucoregulatory activity in patients with type 2 diabetes. Here we report the results of a randomized, open-label, crossover study to assess the relative bioavailability of subcutaneous exenatide injected into arm or thigh vs abdomen. The study enrolled 28 subjects with type 2 diabetes: age 56.2±8.ly; BMI 33.0±5.1 kg/m2; HbA1c, 8.0±1.7% (±SD). Subjects had a single 10 μg injection of exenatide followed by 10 h of plasma sampling. Geometric LS mean exenatide AUC0-infin values were 63935±6608 pg*min/mL (abdomen; ±SEM), 59573±6157 pg*min/mL (arm), 62148±6424 pg*min/mL (thigh). The AUC geometric LS mean ratio for arm vs abdomen was 0.93 with geometric 90% CI ratios of 0.82 to 1.05; and for thigh vs abdomen was 0.97, geometric 90% CI ratios 0.86 to 1.1. Geometric LS mean exenatide Cmax values were 220±24 pg/mL (abdomen), 218±23 pg/mL (arm), and 193±21 pg/mL (thigh). The Cmax geometric LS mean ratio for arm vs abdomen was 0.99 with geometric 90% CI ratios of 0.85 to 1.15, and for thigh vs abdomen was 0.88, geometric 90% CI ratios 0.75 to 1.02. The most common treatment-emergent adverse events were mild-to-moderate nausea, vomiting, and headache. In summary, all injection sites yielded equivalent pharmacokinetic profiles. Clinical Pharmacology & Therapeutics (2004) 75, P58–P58; doi: 10.1016/j.clpt.2003.11.221