Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus

Purpose. The pharmacology and tolerability of exenatide in patients with type 2 diabetes mellitus were studied. Methods. Two randomized, single-blind, placebo-controlled studies were conducted. Treatment with oral antidiabetic agents was stopped 14 days before study initiation. In the first study (study A), eight subjects received placebo, 0.1-, 0.2-, 0.3-, and either 0.4-mug/kg exenatide or placebo five minutes before a meal combined with liquid acetaminophen (to assess the rate of gastric emptying) on days 1, 3, 5,7, and 9. In the second study (study B), subjects received a single s.c. dose of exenatide or placebo on consecutive days. Part 1 of study B used exenatide doses of 0.01 and 0.1 mug/kg; 0.02-, 0.05-, and 0.1-mug/kg doses were given in part 2. After an overnight fast, the study drug was injected 15 minutes before a meal (part 1) and before a meal and acetaminophen (part 2). Parts 1 and 2 of study B enrolled six and eight patients, respectively. Results. In both studies, plasma exenatide pharmacokinetic profiles appeared dose proportional. Exenatide doses of 0.02-0.2 mug/kg dose-dependently lowered postprandial glucose excursions. Exenatide suppressed postprandial plasma glucagon and slowed gastric emptying. There were no serious adverse events and no patient withdrawals related to treatment: Nausea and vomiting were the most common adverse events and were mild to moderate in severity at doses ranging from 0.02 to 0.2 mug/kg. Conclusion. Administration of preprandial exenatide by s.c. injection resulted in dose-proportional exenatide pharmacokinetics and antidiabetic pharmacodynamic activity. At doses ranging from 0.02 to 0.2 mug/kg, exenatide close-dependently reduced postprandial plasma glucose excursion by insulinotropism, suppression of plasma glucagon, and slowing of gastric emptying.