Tolerability and Pharmacokinetics of Lobeglitazone, a Novel Peroxisome Proliferator-Activated Receptor-γ Agonist, After a Single Oral Administration in Healthy Female Subjects

Background and Objectives Lobeglitazone is a recently approved peroxisome proliferator-activated receptor-gamma agonist for the treatment of type 2 diabetes mellitus in Korea. The purpose of this study was to investigate the pharmacokinetic properties of lobeglitazone in healthy females and to compare these with historical data in healthy males. Methods This study was designed as a block-randomized, double-blind, placebo-controlled, parallel-group study. A single 2 or 4 mg oral dose of lobeglitazone or a placebo was randomly administered to 22 female subjects, and pharmacokinetic blood samples were obtained after dosing. Pharmacokinetic parameters were calculated by a non-compartmental method, and the results were compared with those previously obtained from male subjects. Tolerability was assessed by clinical and laboratory parameters. Results During the study, a total of 28 adverse events (AEs) were observed in the lobeglitazone group (n = 16) and nine AEs in the placebo group (n = 6). Serious AEs or significant clinical changes were not observed. After oral administration, lobeglitazone was rapidly absorbed with the time to maximum plasma concentration (t(max)) ranging from 0.5 to 4.0 h. The mean (standard deviation) maximum plasma concentration (C-max) and area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) for the 2 mg dose were 214.8 (56.4) mu g/L and 2,251.3 (721.2) mu g.h/L, respectively, and the corresponding values for the 4 mg dose were 310.0 (47.8) mu g/L and 6,942.6 (1,778.9) mu g . h/L, respectively. The ratios (95 % CIs) for the geometric means (female/male) of the Cmax and AUC(infinity) were 1.23 (0.89-1.69) and 1.11 (0.73-1.68), respectively (2 mg), and 1.28 (1.01-1.63) and 2.36 (1.60-3.47), respectively (4 mg). Conclusion Lobeglitazone was well-tolerated in healthy females. There was no sex difference for systemic lobeglitazone exposure at a 2 mg dose; however, female subjects showed greater systemic exposure than males after the administration of 4 mg of lobeglitazone. In spite of the pharmacokinetic difference, dose adjustment based on sex alone is not needed in clinical use because therapy should be individualized for each patient to achieve glycemic control.