Pharmacokinetics and bioequivalence evaluation of three commercial tablet formulations of mefloquine when given in combination with dihydroartemisinin in patients with acute uncomplicated falciparum malaria

Abstract

Objective: To assess the pharmacokinetics and relative bioavailability/bioequivalence of three commercial tablet formulations of mefloquine, i.e. Lariam (reference formulation), Mephaquin 100 Lactab and Eloquin-250, when given sequentially after dihydroartemisinin in Thai patients with acute uncomplicated falciparum malaria. Methods: Twenty-nine Thai patients with acute uncomplicated falciparum malaria were randomized to receive an initial dose of 300 mg dihydroartemisinin, followed by 1250 mg mefloquine (at 24 h and 30 h after dihydroartemisinin) given as either Lariam (n = 10 cases), Mephaquin (n = 9 cases) or Eloquin-250 (n = 10 cases). Serial blood samples were obtained up to day 42 after treatment with mefloquine. Mefloquine concentrations were determined in whole blood by means of ultraviolet high-performance liquid chromatography. The pharmacokinetic parameters of mefloquine were estimated using non-compartmental and compartmental analysis. Results: The three combination regimens were well tolerated. Patients in all treatment groups had a rapid initial response. However, nine patients (four and five cases in regimen containing Mephaquin 100 Lactab and Eloquin-250, respectively) had reappearance of parasitaemia during the follow-up period. Mefloquine from the three formulations showed significantly different pharmacokinetic and bioavailability metrics. Significantly lower peak plasma concentrations (C(max)) and areas under the plasma concentration-time curve (AUC; AUC(0-48h), AUC(0-7days), and total AUC) were observed with Mephaquin 100 Lactab than with the other two formulations. Mean values for relative bioavailability of the test to standard products were 49.1% (Mephaquin 100 Lactab) and 72.4% (Eloquine-250). Based on the criteria set, the bioavailability of the two test products (Mephaquin 100 Lactab and Eloquine-250) was considered non-equivalent to the reference product with respect to the rate (t(max), C(max)) and extent (AUC(0-48h), AUC(0-7days), total AUC) of mefloquine absorption.