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Pharmacokinetics, Pharmacodynamics, Tolerability, and Safety of Exenatide in Japanese Patients With Type 2 Diabetes Mellitus

From Eli Lilly and Company, Indianapolis, Indiana (Dr Kothare, Dr de la Peña, Dr Mace); Eli Lilly and Company, Windlesham, Surrey, United Kingdom (Dr Linnebjerg); Eli Lilly and Company, Kobe, Japan (Dr Isaka, Mr Uenaka, Mr Yamamura, Dr Shigeta); Lilly-NUS Centre for Clinical Pharmacology, Singapore (Dr Yeo, Dr Teng); Amylin Pharmaceuticals, Inc, San Diego, California (Mr Fineman); PS Clinic, Fukuoka, Japan (Dr Sakata); and Kyushu Clinical Pharmacology Research Clinic, Fukuoka, Japan (Dr Irie).

In this single-blind, parallel, placebo-controlled study, the pharmacokinetics, pharmacodynamics, tolerability, and safety of subcutaneous exenatide were evaluated in 40 Japanese patients with type 2 diabetes. Patients were allocated to 4 groups and randomized to receive exenatide (n = 8/group) or placebo (n = 2/group), with all receiving placebo on day 1. On day 2, patients received single-dose exenatide (2.5 µg [group A] or 5 µg [groups B, C, and D]) or placebo and then bid on days 3 to 5. On days 6 to 10, groups A and B continued on 2.5 and 5 µg bid; groups C and D received 10 and 15 µg bid, respectively. The last dose was given on the morning of day 10. All adverse events were mild or moderate in severity. Exenatide was generally well tolerated up to 10 µg. Exenatide was well absorbed with a median t_max of 1.5 hours and mean t of 1.6 hours; exposure increased with dose. Up to 10 µg, exenatide reduced postprandial glucose concentrations in a dose-dependent fashion compared with placebo; decreases were similar for 10 and 15 µg. An E_max model demonstrated that doses higher than 2.5 µg were necessary for adequate glycemic response. Based on tolerability and pharmacokinetic/pharmacodynamic relationships, 5 and 10 µg exenatide may be considered for further clinical development in Japanese patients with type 2 diabetes.

Key Words: Exenatide • pharmacokinetics • pharmacodynamics • Japanese • type 2 diabetes

Address for reprints: Prajakti Kothare, PhD, Global PK/PD and Trial Simulations, Eli Lilly and Company, Indianapolis, IN 46285; e-mail: kotharep{at}lilly.com.

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