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

Abstract

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 microg [group A] or 5 microg [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 microg bid; groups C and D received 10 and 15 microg 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 microg. Exenatide was well absorbed with a median t(max) of 1.5 hours and mean t((1/2)) of 1.6 hours; exposure increased with dose. Up to 10 microg, exenatide reduced postprandial glucose concentrations in a dose-dependent fashion compared with placebo; decreases were similar for 10 and 15 microg. An E(max) model demonstrated that doses higher than 2.5 microg were necessary for adequate glycemic response. Based on tolerability and pharmacokinetic/pharmacodynamic relationships, 5 and 10 microg exenatide may be considered for further clinical development in Japanese patients with type 2 diabetes.

Exenatide Exhibits Dose-Dependent Effects on Glycemic Control over 12 Weeks in Japanese Patients with Suboptimally Controlled Type 2 Diabetes

“…The safety profile observed in this study was consistent with previous reports for GLP-1 agonists, for both Japanese and non-Japanese populations [8][9][10][11][12][13][14][17][18][19]. Consistent with placebo-controlled studies of exenatide combined with oral antidiabetic agents performed in predominantly Caucasian populations [10][11][12]14] and a study of exenatide performed in 40 Japanese inpatients with type 2 diabetes being treated with either diet and exercise alone or oral antidiabetic agents [8], the treatment-emergent adverse events reported in this study were primarily gastrointestinal in nature, with significant dose-dependent increases in the incidences of nausea, anorexia, decreased appetite, and diarrhea.…”

“…Consistent with placebo-controlled studies of exenatide combined with oral antidiabetic agents performed in predominantly Caucasian populations [10][11][12]14] and a study of exenatide performed in 40 Japanese inpatients with type 2 diabetes being treated with either diet and exercise alone or oral antidiabetic agents [8], the treatment-emergent adverse events reported in this study were primarily gastrointestinal in nature, with significant dose-dependent increases in the incidences of nausea, anorexia, decreased appetite, and diarrhea. a significant dose-dependent increase in the incidence of hypoglycemia was also observed in the current study.…”

“…A randomized, single-blind, placebo-controlled, parallel study has previously evaluated the pharmacokinetics, pharmacodynamics, tolerability, and safety of 2.5 µg, 5 µg, 10 µg, and 15 µg exenatide over a period of 10 days in a group of 40 Japanese inpatients with type 2 diabetes being treated with either diet and exercise alone or oral antidiabetic agents [8]. This study showed that, at doses up to 10 µg, exenatide dose-dependently reduced plasma glucose and was generally well tolerated.…”

“…This study showed that, at doses up to 10 µg, exenatide dose-dependently reduced plasma glucose and was generally well tolerated. The highest dose of exenatide, 15 µg, was poorly tolerated due to nausea and vomiting [8].…”

Evolution of Biochemical Effects of Byetta<sup>®</sup> in Type 2 Diabetics with Cardiovascular Risk

“…The truth is that against the perceived benefits of reducing HbA 1c and body weight, low risk of hypoglycemia (except in combination with a sulfonylurea), low blood pressure and a potential protective effect of β cells, has the following disadvantages: the administration of injections, frequent gastrointestinal side effects, high costs, little experience in treatment, antibody formation and possible interactions with other drugs given delayed gastric emptying. Regarding the cardiovascular risk associated with diabetes mellitus, there is a current controversy, the effects of exenatide, finding favorable effects [15][16][17][18][19][20][21] or on heart rate and blood pressure [15,22,23].…”