ABSTRACT: A randomized, open-label, dose-escalating study was designed to assess the pharmacokinetics, pharmacodynamics and tolerability of single and multiple subcutaneous administrations of exenatide in 24 healthy Chinese volunteers. The effects of gender on the pharmacokinetics of exenatide were also evaluated. Subjects were randomized to receive a single and multiple subcutaneous doses of 5 or 10 μg of exenatide. Following the single dose subjects received exenatide twice daily on days 2-4 and once on day 5. Sequential blood samples were collected at regular intervals from 0 to 8 h after single administration. Concomitantly the serum glucose concentrations were measured in each sample. Tolerability was assessed using physical examination, vital signs, laboratory analysis, and by interview of subjects. Pharmacokinetic parameters for exenatide after subcutaneous administration of a single dose of 5-10 μg were as follows: Cmax=77.7 (13.9) and 136.1 (15.2) pg/mL; AUC0-t=184.2 (49.7) and 309.7 (52.3) pg·h/mL; AUC0-∞=225.8 (77.4) and 365.4 (68.8) pg·h/mL; tmax (median [range])=1.00 (0.75-1.50) and 1.00 (0.75-1.50) h; t1/2 (mean [range])=1.4 (0.7-3.2) and 1.8 (1.0-2.5) h, respectively. Because of its short t1/2, Css, min could not be detected in any plasma samples prior to daily dosing on days 3-5. Pharmacokinetic parameters for exenatide after administration of multiple doses of 5 or 10 μg were as follows: Cmax=81.2 (12.2) and 144.5 (13.3) pg/mL; AUC0-t=181.1 (39.4) and 275.6 (45.0) pg·h/mL; AUC0-∞=217.2 (44.8) and 313.3 (48.4) pg·h/mL; tmax=1.10 (0.75-1.25) and 1.00 (1.00-1.25) h; t1/2=1.6 (0.8-2.2) and 1.4 (0.9-2.7) h, respectively. Both doses of exenatide were associated with significant reductions in serum glucose concentrations (P<0.001) when compared to baseline levels. Mean percentage of maximal decline for serum glucose concentrations after single and multiple doses were 15.6% and 19.9% for 5 μg, respectively; as well as 26.3% and 28.7% for 10 μg, respectively. 12 of the 24 subjects reported a total of 75 adverse events. The rate increased with higher doses of exenatide: after 5 μg only one subject experienced at least 1 adverse event but following 10 μg 11 subjects were affected. 2 subjects receiving the higher dose of 10 μg exenatide dropped out because of adverse events (nausea and vomiting). The most common adverse events were of gastrointestinal origin (e. g. decreased appetite, nausea and vomiting) and of mild severity. In conclusion, in healthy Chinese subjects, AUC and Cmax increased in proportion to the dose, whereas t1/2 was independent of dose. The pharmacokinetic parameters after multiple dosing were consistent with those after single doses. No significant gender differences were noted for pharmacokinetic variables. Both exenatide doses were associated with significant reductions in serum glucose levels. Adverse events were mainly of gastrointestinal origin and their incidence was dose-dependent.
Arzneimittel-Forschung 01/2012; 62(2):75-82. · 0.72 Impact Factor