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 artemether-lumefantrine are lipophilic, with the possibility that recommended fixed doses in adults may lead to sub-therapeutic 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 or obese healthy male volunteers (body mass index [BMI] categories ≤25 kg/m², >25 to ≤30 kg/m², and >30 kg/m², respectively; absolute range 19.3 to 37.2 kg/m²). Participants received the conventional six doses of artemether-lumefantrine over three 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 time-points over 14 days. Plasma drug/metabolite concentrations were measured using liquid chromatography-mass 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 ARM which was attenuated when normalised 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 µg/L (the threshold at which Plasmodium falciparum recrudescences are minimised) in all participants. These results indicate that there is no need for artemether-lumefantrine dose modification in overweight and obese patients with malaria.