Pharmacokinetic properties of the antimalarial combination therapy artemether-lumefantrine in normal-weight, overweight and obese healthy male adults

The component drugs in the widely used antimalarial artemisinin combination therapy artemetherlumefantrine are lipophilic, with the possibility that recommended fixed doses in adults may lead to subtherapeutic concentrations and consequent treatment failure in overweight/obese individuals with malaria. The aim of this study was to investigate the pharmacokinetic properties of artemether, lumefantrine and their active metabolites dihydroartemisinin and desbutyl-lumefantrine in 16 normal-weight, overweight and obese healthy male volunteers [body mass index (BMI) categories <= 25 kg/m(2), >25-<= 30 kg/m(2) and >30 kg/m(2), respectively; absolute range 19.3-37.2 kg/m(2)]. Participants received the conventional six doses of artemether-lumefantrine over 3 days, each dose comprising 80 mg artemether plus 480 mg lumefantrine administered with 6.7 g fat, and blood samples were collected at pre-specified timepoints over 14 days. Plasma drug/metabolite concentrations were measured using liquid chromatographymass spectrometry and included in multi-compartmental population pharmacokinetic models. There was a non-significant trend to a lower area under the plasma concentration-time curve with a higher body weight or BMI for dihydroartemisinin and especially artemether which was attenuated when normalized for mg/kg dose, but this relationship was not evident in the case of the more lipophilic lumefantrine and its metabolite desbutyl-lumefantrine. Simulated Day 7 plasma lumefantrine concentrations were >200 mu g/L (the threshold at which Plasmodium falciparum recrudescences are minimized) in all participants. These results indicate that there is no need for artemether-lumefantrine dose modification in overweight and obese patients with malaria. (C) 2021 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.

Automated summary

This study investigated the pharmacokinetic properties of artemether, lumefantrine, and their active metabolites in individuals with different body weights. The results indicate that dose modification of artemether-lumefantrine is not necessary for overweight and obese patients with malaria.