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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].).
AuthorsFrank Kloprogge, Rose McGready, Warunee Hanpithakpong, Daniel Blessborn, Nicholas P J Day, Nicholas J White, François Nosten, Joel Tarning
JournalAntimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 59 Issue 10 Pg. 6375-84 (Oct 2015) ISSN: 1098-6596 [Electronic] United States
PMID26239986 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015, Kloprogge et al.
Chemical References
  • Antimalarials
  • Ethanolamines
  • Fluorenes
  • desbutyllumefantrine
  • Lumefantrine
Topics
  • Adolescent
  • Adult
  • Antimalarials (blood, pharmacokinetics, pharmacology)
  • Computer Simulation
  • Drug Administration Schedule
  • Ethanolamines (blood, pharmacokinetics, pharmacology)
  • Female
  • Fluorenes (blood, pharmacokinetics, pharmacology)
  • Humans
  • Lumefantrine
  • Malaria, Falciparum (diagnosis, drug therapy, parasitology)
  • Models, Statistical
  • Myanmar
  • Plasmodium falciparum (drug effects, physiology)
  • Pregnancy
  • Recurrence
  • Thailand
  • Treatment Outcome

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