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Copyright © 2005 by American Society of Health-System Pharmacists
Reports |
Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus
ORVILLE G. KOLTERMAN, M.D., is Senior Vice-President, Clinical Affairs; DENNIS D. KIM, M.D., is Senior Director, Medical Affairs; LARRY SHEN, PH.D., is Senior Director, Biometrics; JAMES A. RUGGLES, PH.D., is Associate Director Medical Writing, Medical Affairs; LORETTA L. NIELSEN, PH.D., is Senior Medical Writer, Medical Affairs; MARK S. FINEMAN, B.S., is Senior Director, Clinical Affairs; and ALAIN D. BARON, M.D., is Senior Vice-President Research, Amylin Pharmaceuticals Inc., San Diego, CA.
Address correspondence to Dr. Kolterman at Amylin Pharmaceuticals Inc., 9360 Towne Centre Drive, Suite 110, San Diego, CA 92121 (okolterman{at}amylin.com).
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-µg/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 µg/ kg; 0.02-, 0.05-, and 0.1-µg/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 µg/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 µg/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 µg/kg, exenatide dose-dependently reduced postprandial plasma glucose excursion by insulinotropism, suppression of plasma glucagon, and slowing of gastric emptying.
Index terms: Antidiabetic agents; Blood levels; Diabetes mellitus; Dosage; Drug administration routes; Exenatide; Gastric emptying; Mechanism of action; Pharmacodynamics; Pharmacokinetics; Toxicity
Purpose. The pharmacology and tolerability of exenatide in patients with type 2 diabetes mellitus were studied.
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