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Population pharmacokinetics of mefloquine, piperaquine and artemether-lumefantrine in Cambodian and Tanzanian malaria patients

Staehli Hodel, Eva Maria and Guidi, Monia and Zanolari, Boris and Mercier, Thomas and Duong, Socheat and Kabanywanyi, Abdunoor M. and Ariey, Frédéric and Buclin, Thierry and Beck, Hans-Peter and Decosterd, Laurent A. and Olliaro, Piero and Genton, Blaise and Csajka, Chantal. (2013) Population pharmacokinetics of mefloquine, piperaquine and artemether-lumefantrine in Cambodian and Tanzanian malaria patients. Malaria journal, Vol. 12 , 235.

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Official URL: http://edoc.unibas.ch/dok/A6165029

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Abstract

Inter-individual variability in plasma concentration-time profiles might contribute to differences in anti-malarial treatment response. This study investigated the pharmacokinetics of three different forms of artemisinin combination therapy (ACT) in Tanzania and Cambodia to quantify and identify potential sources of variability.; Drug concentrations were measured in 143 patients in Tanzania (artemether, dihydroartemisinin, lumefantrine and desbutyl-lumefantrine), and in 63 (artesunate, dihydroartemisinin and mefloquine) and 60 (dihydroartemisinin and piperaquine) patients in Cambodia. Inter- and intra-individual variabilities in the pharmacokinetic parameters were assessed and the contribution of demographic and other covariates was quantified using a nonlinear mixed-effects modelling approach (NONMEM®).; A one-compartment model with first-order absorption from the gastrointestinal tract fitted the data for all drugs except piperaquine (two-compartment). Inter-individual variability in concentration exposure was about 40% and 12% for mefloquine. From all the covariates tested, only body weight (for all antimalarials) and concomitant treatment (for artemether only) showed a significant influence on these drugs' pharmacokinetic profiles. Artesunate and dihydroartemisinin could not be studied in the Cambodian patients due to insufficient data-points. Modeled lumefantrine kinetics showed that the target day 7 concentrations may not be achieved in a substantial proportion of patients.; The marked variability in the disposition of different forms of ACT remained largely unexplained by the available covariates. Dosing on body weight appears justified. The concomitance of unregulated drug use (residual levels found on admission) and sub-optimal exposure (variability) could generate low plasma levels that contribute to selecting for drug-resistant parasites.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Epidemiology and Public Health (EPH) > Health Interventions > Clinical Epidemiology (Genton)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
UniBasel Contributors:Beck, Hans-Peter and Genton, Blaise
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:BioMed Central
ISSN:1475-2875
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:31 Jan 2014 09:49
Deposited On:31 Jan 2014 09:49

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