The pharmacokinetic properties of artemether and lumefantrine in Malaysian patients with Plasmodium knowlesi malaria.

Autor: Sugiarto SR; University of Western Australia, Medical School, Fremantle Hospital, Fremantle, Western Australia, Australia., Singh B; Universiti Malaysia Sarawak (UNIMAS) Malaria Research Centre, Kota Samarahan, Sarawak, Malaysia., Page-Sharp M; School of Pharmacy, Curtin University of Technology, Bentley, 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, PathWest, Nedlands, Western Australia, Australia.; Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, Perth, Western Australia, Australia., Hii KC; Kapit Hospital, Kapit, Sarawak, Malaysia., Davis TME; University of Western Australia, Medical School, Fremantle Hospital, Fremantle, Western Australia, Australia.
Jazyk: angličtina
Zdroj: British journal of clinical pharmacology [Br J Clin Pharmacol] 2022 Feb; Vol. 88 (2), pp. 691-701. Date of Electronic Publication: 2021 Aug 12.
DOI: 10.1111/bcp.15001
Abstrakt: Aims: The aim of this study was to assess the pharmacokinetic properties of artemether, lumefantrine and their active metabolites in Plasmodium knowlesi malaria.
Methods: Malaysian adults presenting with uncomplicated P. knowlesi infections received six doses of artemether (1.7 mg/kg) plus lumefantrine (10 mg/kg) over 3 days. Venous blood and dried blood spot (DBS) samples were taken at predetermined time-points over 28 days. Plasma and DBS artemether, dihydroartemisinin, lumefantrine and desbutyl-lumefantrine were measured using liquid chromatography-mass spectrometry. Multi-compartmental population pharmacokinetic models were developed using plasma with or without DBS drug concentrations.
Results: Forty-one participants (mean age 45 years, 66% males) were recruited. Artemether-lumefantrine treatment was well tolerated and parasite clearance was prompt. Plasma and DBS lumefantrine concentrations were in close agreement and were used together in pharmacokinetic modelling, but only plasma concentrations of the other analytes were used because of poor correlation with DBS levels. The areas under the concentration-time curve (AUC 0-∞ ) for artemether, dihydroartemisinin and lumefantrine (medians 1626, 1881 and 625 098 μg.h/L, respectively) were similar to those reported in previous pharmacokinetic studies in adults and children. There was evidence of auto-induction of artemether metabolism (mean increase in clearance relative to bioavailability 25.2% for each subsequent dose). The lumefantrine terminal elimination half-life (median 9.5 days) was longer than reported in healthy volunteers and adults with falciparum malaria.
Conclusion: The disposition of artemether, dihydroartemisinin and lumefantrine in knowlesi malaria largely parallels that in other human malarias. DBS lumefantrine concentrations can be used in pharmacokinetic studies but DBS technology is currently unreliable for the other analytes.
(© 2021 British Pharmacological Society.)
Databáze: MEDLINE
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