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

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.