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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Population pharmacokinetics and pharmacodynamics of artemether and lumefantrine during combination treatment in children with uncomplicated falciparum malaria in Tanzania
Antimicrobial Agents and Chemotherapy, Volume 54, No. 11, Year 2010
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Description
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.
Authors & Co-Authors
Hietala, Sofia Friberg
Sweden, Gothenburg
Sahlgrenska Akademin
Mårtensson, Andreas A.
Sweden, Stockholm
Karolinska Universitetssjukhuset
Sweden, Stockholm
Karolinska Institutet
Ngasala, Billy E.
Tanzania, Dar es Salaam
Muhimbili University of Health and Allied Sciences
Dahlström, Sabina
Sweden, Stockholm
Karolinska Universitetssjukhuset
Lindegårdh, Niklas
Thailand, Nakhon Pathom
Mahidol University
United Kingdom, Oxford
Nuffield Department of Medicine
Annerberg, Anna
Thailand, Nakhon Pathom
Mahidol University
Premji, Zulfiqarali G.
Tanzania, Dar es Salaam
Muhimbili University of Health and Allied Sciences
Färnert, Anna
Sweden, Stockholm
Karolinska Universitetssjukhuset
Gil, Jose Pedro
Sweden, Stockholm
Karolinska Universitetssjukhuset
Portugal, Faro
Universidade do Algarve
Bjǒrkman, Anders B.
Sweden, Stockholm
Karolinska Universitetssjukhuset
Ashton, Michael
Sweden, Gothenburg
Sahlgrenska Akademin
Statistics
Citations: 56
Authors: 11
Affiliations: 7
Identifiers
Doi:
10.1128/AAC.00252-10
ISSN:
00664804
e-ISSN:
10986596
Research Areas
Health System And Policy
Infectious Diseases
Maternal And Child Health
Study Design
Cross Sectional Study
Study Locations
Tanzania