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

Autor: Sugiarto SR; University of Western Australia, Medical School, Fremantle Hospital, Fremantle, Western Australia, Australia., Page-Sharp M; Curtin University, School of Pharmacy and Biomedical Sciences, Bentley, Western Australia, Australia., Drinkwater JJ; University of Western Australia, Medical School, Fremantle Hospital, Fremantle, Western Australia, Australia., Davis WA; University of Western Australia, Medical School, Fremantle Hospital, Fremantle, Western Australia, Australia., Salman S; University of Western Australia, Medical School, Fremantle Hospital, Fremantle, Western Australia, Australia; Clinical Pharmacology and Toxicology Unit, PathWest, Western Australia, Australia., Davis TME; University of Western Australia, Medical School, Fremantle Hospital, Fremantle, Western Australia, Australia. Electronic address: tim.davis@uwa.edu.au.
Jazyk: angličtina
Zdroj: International journal of antimicrobial agents [Int J Antimicrob Agents] 2022 Jan; Vol. 59 (1), pp. 106482. Date of Electronic Publication: 2021 Nov 21.
DOI: 10.1016/j.ijantimicag.2021.106482
Abstrakt: 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 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/m², >25-≤30 kg/m² and >30 kg/m², respectively; absolute range 19.3-37.2 kg/m²]. 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 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 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 µg/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.
(Copyright © 2021 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)
Databáze: MEDLINE
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