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Title: Population pharmacokinetics and pharmacodynamics of artemether and lumefantrine during combination treatment in children with uncomplicated falciparum malaria in Tanzania
Authors: Sofia Friberg Hietala
Andreas Mårtensson
Billy Ngasala
Sabina Dahlström
Niklas Lindegårdh
Anna Annerberg
Zul Premji
Anna Färnert
Pedro Gil
Anders Björkman
Michael Ashton
Goteborg University, Sahlgrenska Academy
Karolinska University Hospital
Karolinska Institutet
Muhimbili University of Health and Allied Sciences
Mahidol University
Nuffield Department of Clinical Medicine
Universidade do Algarve
Keywords: Medicine;Pharmacology, Toxicology and Pharmaceutics
Issue Date: 1-Nov-2010
Citation: Antimicrobial Agents and Chemotherapy. Vol.54, No.11 (2010), 4780-4788
Abstract: The combination of artemether (ARM) and lumefantrine is currently the first-line treatment of uncomplicated falciparum malaria in mainland Tanzania. While the exposure to lumefantrine has been associated with the probability of adequate clinical and parasitological cure, increasing exposure to artemether and the active metabolite dihydroartemisinin (DHA) has been shown to decrease the parasite clearance time. The aim of this analysis was to describe the pharmacokinetics and pharmacodynamics of artemether, dihydroartemisinin, and lumefantrine in African children with uncomplicated malaria. In addition to drug concentrations and parasitemias from 50 Tanzanian children with falciparum malaria, peripheral parasite densities from 11 asymptomatic children were included in the model of the parasite dynamics. The population pharmacokinetics and pharmacodynamics of artemether, dihydroartemisinin, and lumefantrine were modeled in NONMEM. The distribution of artemether was described by a two-compartment model with a rapid absorption and elimination through metabolism to dihydroartemisinin. Dihydroartemisinin concentrations were adequately illustrated by a one-compartment model. The pharmacokinetics of artemether was time dependent, with typical oral clearance increasing from 2.6 liters/h/kg on day 1 to 10 liters/h/kg on day 3. The pharmacokinetics of lumefantrine was sufficiently described by a one-compartment model with an absorption lag time. The typical value of oral clearance was estimated to 77 ml/h/kg. The proposed semimechanistic model of parasite dynamics, while a rough approximation of the complex interplay between malaria parasite and the human host, adequately described the early effect of ARM and DHA concentrations on the parasite density in malaria patients. However, the poor precision in some parameters illustrates the need for further data to support and refine this model. Copyright © 2010, American Society for Microbiology. All Rights Reserved.
ISSN: 10986596
Appears in Collections:Scopus 2006-2010

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