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Oral Antidiabetic Drugs: Bioavailability Assessment of Fixed-Dose Combination Tablets of Pioglitazone and Metformin. Effect of Body Weight, Gender, and Race on Systemic Exposures of Each Drug

From Takeda Global Research & Development Center, Inc, Lincolnshire, Illinois (Dr Karim, Ms Slater, Ms Bradford, Ms Schwartz, Ms Zhao, Dr Cao) and PPD Development, LP, Austin, Texas (Dr Laurent).

Bioavailability of pioglitazone and metformin, in 2 dose strengths, given either as a fixed-dose combination tablet or as coadministration of commercial tablets (coad), was studied in young healthy subjects in 2 separate studies. In study I (n = 63), single oral doses of 15-mg pioglitazone/500-mg metformin fixed-dose combination tablets or equivalent doses of commercial tablets were administered, in a fasting state, in an open-label, randomized, crossover study with a 7-day washout period between treatments. Study II (n = 61) was similar in design to study I, except the 15/850-mg fixed-dose combination tablet and coad treatments were evaluated. Least squares mean (fixed-dose combination/coad) ratios and 90% confidence intervals of the ratios for the 15/500-mg dose strength for the maximum observed serum concentration (C_max) and area under the serum concentration-time curve from time 0 to infinity (AUC) were 0.95 (0.86-1.05) and 1.02 (0.98-1.08), respectively, for pioglitazone and 0.99 (0.95-1.03) and 1.03 (0.98-1.08), respectively, for metformin. Bioequivalency for pioglitazone and metformin between fixed-dose combination tablets and coad treatments was met for both strengths of fixed-dose combination tablets. In a post hoc metaanalysis of combined data from the 2 studies (n = 124), there was considerable overlapping in AUC values between gender and race (Caucasians, Blacks, and Hispanics), making neither gender-nor racial-based dosing of pioglitazone or metformin necessary.

Key Words: oral antidiabetic drugs • pioglitazone • metformin • fixed-dose combination tablets • effect of body weight, gender, and race on systemic exposures

Address for reprints: Aziz Karim, PhD, ABCP, FCP, Takeda Global Research & Development Center, Inc, 475 Half Day Road, Lincolnshire, IL 60069; e-mail: akarim{at}tgrd.com.