Abstract
BackgroundLow mefloquine exposure has been shown to contribute to treatment failure in patients with uncomplicated falciparum malaria following a 3-day artesunate–mefloquine combination. The present study aimed to develop a population pharmacokinetic model for mefloquine based on whole blood concentration–time profiles of this target population for further dose optimization.MethodsA total of 129 Burmese patients aged above 15 years who presented with typical symptoms of malaria and had a blood smear positive for Plasmodium falciparum were included in the study. All were treated with the standard 3-day combination regimen of artesunate and mefloquine consisting of mefloquine for 2 days and artesunate for 3 days. Blood samples were collected before and at different time points after drug administration from different sub-groups of patients. Mefloquine concentrations were quantified in whole blood using high-performance liquid chromatography. A non-linear mixed-effect modelling approach was applied for population pharmacokinetic analysis using the NONMEM v7.3 software. Covariates investigated (body weight, gender, admission parasitaemia, and molecular markers of mefloquine resistance) were investigated in a step-wise manner using the SCM functionality in Perl-Speaks-NONMEM.ResultsPopulation pharmacokinetic analysis of mefloquine was performed in all patients with a total of 653 samples. Whole blood mefloquine concentration–time profiles were described by a two-compartment disposition model. Of the covariates investigated, none was found to have a significant impact on the pharmacokinetics of mefloquine. Significant differences in maximum concentration (Cmax) and elimination half-life (t1/2) were found in patients who had treatment failure (36 cases) compared to patients with successful treatment (107 cases).ConclusionThe study successfully describes the pharmacokinetics of mefloquine following a 2-day treatment of mefloquine as a part of a 3-day artesunate–mefloquine in patients with uncomplicated falciparum malaria from Thailand. A model has been developed which adequately describes the pharmacokinetics of mefloquine. More extensive clinical studies including both adults and children are needed to fully characterize the pharmacokinetics of mefloquine.
Highlights
Low mefloquine exposure has been shown to contribute to treatment failure in patients with uncom‐ plicated falciparum malaria following a 3-day artesunate–mefloquine combination
The present study aimed to develop a population pharmacokinetic model for mefloquine based on data from adults with uncomplicated falciparum malaria in Thailand
Pharmacokinetic model Population pharmacokinetic analysis of mefloquine was performed in 129 Burmese patients with uncomplicated falciparum malaria with a total of 653 data points
Summary
Low mefloquine exposure has been shown to contribute to treatment failure in patients with uncom‐ plicated falciparum malaria following a 3-day artesunate–mefloquine combination. ACT consists of an artemisinin drug with a potent schizonticidal activity, together with a long elimination half-life partner drug, which is present in the blood at therapeutic concentrations for at least several of the parasite life cycles to prevent recrudescence [4]. These combinations have been shown to result in welltolerated anti-malarial treatment, which acts rapidly and has a reliable and sustained efficacy. Artemisinin resistance has emerged during the last decade and has spread within southeast Asia [5]
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