Bioequivalence assessment of pioglitazone hydrochloride oral preparation by limited sampling strategy

AimTo develop limited sampling strategy (LSS) for estimation ofC_max and AUC0-t and assessing the bioequivalence of two pioglitazone hydrochloride (PGT) preparations. MethodsHealthy subjects (n=20), enrolled in a bioequivalence study, were received 30 mg PGT po of reference or test formulation. The plasma concentration of PGT was determined by the validated HPLC method. A multiple linear regression analysis of theC_max and AUC_0-t against the PGT concentration for the reference formulation was carried out to develop LSS models to estimate these parameters. The models were internally validated by the Jackknife method and externally validated using simulated sets generated by Monte Carlo method. The best model was employed to assess bioequivalence of the two PGT formulations. Results The linear relationship between pharmacokinetics parameters and single concentration point was poor. Several models for these parameters estimation met the predefined criteria (r²>0.9). The Jackknife validation procedure revealed that LSS models based on two sampling times (C₁,C_2.5 andC_1.5,C_2.5 forC_max;C_1.5,C₉ andC_2.5,C_{9 for AUC}0-t) predict accurately. Mean prediction errors (MPE) were less than 3%, and mean absolute prediction error (MAE) were less than 9%. The prediction error (PE) beyond 20% was less than 5% of total samples. Model external validation by Monte Carlo simulated data indicated that the most informative sampling combinations wereC_1.5,C_2.5 forC_max, andC_1.5,C_{9 for AUCZ}0-t respectively. MPE and MAE of the proposed models were less than 5%, and 9% respectively. The PE beyond 20% was less than 5% of the total. Bioequivalence assessment of the two PGT formulations, based on the best LSS models, provided results similar to those obtained using all the observed concentration-time data points, and indicated that the two PGT formulations were bioequivalent. ConclusionThe LSS method for bioequivalence assessment of PGT formulations was established and proved to be applicable and accurate. Thus, it could be considered appropriate for PGT bioequivalence study with inexpensive cost of sampling acquisition and analysis.