The effect of mefloquine on artesunate pharmacokinetics was assessed in 20 volunteers given artesunate for 3 days, followed >21 days later by combination therapy for 3 days. The areas under the concentration-time curve from 0 h to infinity for dihydroartemisinin, the active metabolite of artesunate, were similar on day 3 of the two dosing periods (P ؍ 0.12), implying no interaction.Mefloquine-artesunate was one of the first artemisinin combination therapies used clinically, and it remains an effective treatment for uncomplicated malaria (2, 9). While the influence of artesunate on the pharmacokinetics of mefloquine has been investigated (12, 16), with seemingly inconsistent results (11), the effect of mefloquine on artesunate disposition has not. The active metabolite of artesunate, dihydroartemisinin (DHA), is itself an antimalarial drug that has been partnered with mefloquine as a form of artemisinin combination therapy (2, 9). Mefloquine does not influence DHA pharmacokinetics in patients with falciparum malaria (13-15), but extrapolation of this finding to artesunate-mefloquine may be invalid. Artesunate and DHA have different chemical and pharmacologic properties (5), and between-subject variability and changes in drug disposition and metabolism during recovery from malaria complicate assessment of previously published parallel-group DHA-mefloquine patient studies. We have therefore evaluated the effects of mefloquine on artesunate and DHA pharmacokinetics in healthy males, using a crossover study design.The study was approved by the South Metropolitan Health Service Human Research Ethics Committee, Western Australia, and all subjects provided informed consent. Twenty of the 25 volunteers recruited met eligibility criteria and provided complete valid data for analysis. Their mean age was 28.9 (range, 19.0 to 57.1) years and their mean body weight 77 (48 to 130) kg. Each subject received 200 mg artesunate (Mepha Ltd., Switzerland) by mouth after an overnight fast on three consecutive mornings (period 1). After a washout phase of Ն21 days, this schedule was repeated, but mefloquine (Mepha) at 250 mg daily was given at the same time as artesunate (period 2). On days 1 and 3 of each period, blood samples were drawn for drug assay under a predetermined schedule from immediately before (0 h) to 8 h postdose. Additional samples were taken for mefloquine assay on the mornings of days 2, 4, 5, and 6 during and after period 2.Drug assays were by high-performance liquid chromatography. For mefloquine, extracted plasma (with clomipramine as an internal standard) was injected onto a RP Select B column (E. Merck, Darmstadt, Germany) run on a 1100 high-performance liquid chromatograph (Agilent Technologies, Waldbronn, Germany), using a mobile phase of 40% (vol/vol) acetonitrile in 45 mM KH 2 PO 4 (pH 3) at 1.3 ml/min with UV detection at 225 nm. Within-and between-day relative standard deviations over 50 to 2,000 g/liter were Յ9.4% and Յ8.8%, respectively. The lower limit of quantitation was 10 g/liter. For artesunate a...
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