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Replicate Study Design in Bioequivalency Assessment, Pros and Cons: Bioavailabilities of the Antidiabetic Drugs Pioglitazone and Glimepiride Present in a Fixed-Dose Combination Formulation

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

An open-label, randomized, 2-sequence, 4-period crossover (7-day washout period between treatment), replicate design study was conducted in 37 healthy subjects to assess intersubject and intrasubject variabilities in the peak (C_max) and total (AUC) exposures to 2 oral antidiabetic drugs, pioglitazone and glimepiride, after single doses of 30 mg pioglitazone and 4 mg glimepiride, given under fasted state, as commercial tablets coadministered or as a single fixed-dose combination tablet. Variabilities for AUC for coadministered and fixed-dose combination treatments were similar: 16% to 19% (intra) and 23% to 25% (inter) for pioglitazone and 18% to 19% (intra) and 29% to 30% for glimepiride (inter, excluding 1 poor metabolizer). Fixed-dose combination/coadministered least squares mean ratios of 0.86 and the 90% confidence intervals of these ratios for pioglitazone and glimepiride of between 0.80 and 1.25 for C_max, AUC_lqc, and AUC met the bioequivalency standards. Gender analysis showed that women showed mean of 16% and 30% higher exposure than men for glimepiride (excluding 1 poor metabolizer) and pioglitazone, respectively. There was considerable overlapping in the AUC values, making gender-dependent dosing unnecessary. Patients taking pioglitazone and glimepiride as cotherapy may replace their medication with a single fixed-dose combination tablet containing these 2 oral antidiabetic drugs.

Key Words: Fixed-dose combination • oral antidiabetics • pioglitazone • glimepiride • intersubject and intrasubject systemic exposure variability • bioequivalency • replicate study design

Address for correspondence: Aziz Karim, PhD, ABCP, FCP, Takeda Global Research & Development Center, Inc, One Takeda Parkway, Deerfield, IL 60015; e-mail: akarim{at}tgrd.com.