Lack of bioequivalence of a generic mefloquine tablet with the standard product

Objective: To assess the bioequivalence between a generic tablet of mefloquine (Mephaquin^®?= M1) with the reference tablet (Lariam^®?=?M2) in healthy volunteers. Methods: This open label, randomized two-way cross-over study was performed in a single centre. Following an overnight fast, eighteen healthy volunteers received a single oral dose of 750?mg mefloquine either in the form of three M1 lactabs or three M2 tablets. Serial blood samples were collected up to 8 weeks after drug administration. Plasma samples were analysed for mefloquine and its carboxylic acid metabolite using liquid chromatography and subsequent tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters of mefloquine and its metabolite were estimated by non-compartmental methods. Results: The pharmacokinetics of mefloquine after administration of M1 and M2 tablets were significantly different as reflected by the respective mean values of maximum plasma concentration (C_max 656 vs 1018?ng?·?ml^?1), time to reach maximum concentration (t_max 46 vs 13?h) and area under the plasma concentration-time curve (AUC_0→∞ 338 vs 432?μg?·?h?·?ml^?1). No significant differences existed between the elimination half-lives of the two formulations (394 vs 396?h). The relative bioavailability (M1 vs M2) was 0.78 and ranged from 0.38 to 1.37. Bioequivalence could not be demonstrated for log-transformed data of AUC_0→∞ or AUC_0→last within a predefined range of 80–125% and for C_max within a range of 70–143%. Conclusions: The observed differences in C_max, t_max and AUC are consistent with a slower rate and lower extent of mefloquine absorption after administration of M1. Statistical evaluation of these kinetic data showed that the M1 tablet is not bioequivalent to the M2 tablet. Clinical consequences of this finding cannot be excluded.