title: Lumefantrine and Desbutyl-Lumefantrine Population Pharmacokinetic-Pharmacodynamic Relationships in Pregnant Women with Uncomplicated Plasmodium falciparum Malaria on the Thailand-Myanmar Border.
abstract: Artemether-lumefantrine is the most widely used antimalarial artemisinin-based combination treatment. Recent studies have suggested that day 7 plasma concentrations of the potent metabolite desbutyl-lumefantrine correlate better with treatment outcomes than those of lumefantrine. Low cure rates have been reported in pregnant women with uncomplicated falciparum malaria treated with artemether-lumefantrine in northwest Thailand. A simultaneous pharmacokinetic drug-metabolite model was developed based on dense venous and sparse capillary lumefantrine and desbutyl-lumefantrine plasma samples from 116 pregnant patients on the Thailand-Myanmar border. The best model was used to evaluate therapeutic outcomes with a time-to-event approach. Lumefantrine and desbutyl-lumefantrine concentrations, implemented in an Emax model, both predicted treatment outcomes, but lumefantrine provided better predictive power. A combined model including both lumefantrine and desbutyl-lumefantrine did not improve the model further. Simulations suggested that cure rates in pregnant women with falciparum malaria could be increased by prolonging the treatment course. (These trials were registered at controlled-trials.com [ISRCTN 86353884].).
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom WorldWide Antimalarial Resistance Network (WWARN), Oxford, United Kingdom.
authors.forename: Frank
authors.initials: F
authors.lastname: Kloprogge
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand Shoklo Malaria Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Rose
authors.initials: R
authors.lastname: McGready
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Warunee
authors.initials: W
authors.lastname: Hanpithakpong
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Daniel
authors.initials: D
authors.lastname: Blessborn
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Nicholas P J
authors.initials: NP
authors.lastname: Day
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand Shoklo Malaria Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: François
authors.initials: F
authors.lastname: Nosten
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand WorldWide Antimalarial Resistance Network (WWARN), Oxford, United Kingdom joel@tropmedres.ac.
authors.forename: Joel
authors.identifier: http://orcid.org/0000-0003-4566-4030
authors.initials: J
authors.lastname: Tarning
mesh_terms: D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D003198:Computer Simulation; D004334:Drug Administration Schedule; D004983:Ethanolamines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D005449:Fluorenes / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D000078102:Lumefantrine; D016778:Malaria, Falciparum / Q000175:diagnosis / Q000188:drug therapy* / Q000469:parasitology; D015233:Models, Statistical; D002052:Myanmar; D010963:Plasmodium falciparum / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D012008:Recurrence; D013785:Thailand; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D004983:Ethanolamines; D005449:Fluorenes; C535063:desbutyllumefantrine; D000078102:Lumefantrine