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Oral Antidiabetic Drugs: Effect of Food on Absorption of Pioglitazone and Metformin From a Fixed-Dose Combination Tablet

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

An open-label, randomized, crossover study involving 28 healthy subjects was conducted to compare the peak (C_max) and total (AUC_lqc, AUC) exposures to pioglitazone and metformin after single-dose administration of a fixed-dose combination tablet containing 15 mg of pioglitazone plus 850 mg metformin when given under fasted versus fed states, with a washout period of 7 days between treatments. Two different fixed-dose combination formulations (bilayer and pioglitazone-micronized fixed-dose combination tablets) were tested. The pioglitazone-micronized fixed-dose combination formulation was selected for clinical development and regulatory approval; the present study describes food effect results with this formulation. For pioglitazone, least squares mean ratios (fed/fasted) and the 90% confidence intervals of these ratios were 1.05 (0.93-1.18) for C_max, 1.13 (1.02-1.25) for AUC_lqc, and 1.11 (1.01-1.22) for AUC. For metformin, these values were 0.72 (0.65-0.79) for C_max, 0.87 (0.81-0.94) for AUC_lqc, and 0.87 (0.81-0.94) for AUC. Dosing with food resulted in median prolongation of t_max values by 1.5 hours for metformin and 2.0 hours for pioglitazone. Because bioequivalency criteria were met (fed/fasted 90% confidence interval between 0.80 and 1.25) for both pioglitazone and metformin AUC, fixed-dose combination tablets can be taken with or without food, but to minimize gastrointestinal adverse effects of metformin, the fixed-dose combination tablets are recommended to be taken with food.

Key Words: oral antidiabetic drugs • pioglitazone • metformin • fixed-dose combination tablets • food effect

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.

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