Population pharmacokinetics of mefloquine, piperaquine and artemether-lumefantrine in Cambodian and Tanzanian malaria patients
- Equal contributors
1 Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland
2 School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
3 Division of Clinical Pharmacology and Toxicology, Department of Laboratories, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
4 National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia
5 Ifakara Health Institute, Dar es Salaam, Tanzania
6 Institut Pasteur in Cambodia, Molecular Epidemiology UnitInstitut Pasteur in Cambodia, Molecular Epidemiology Unit, Phnom Penh, Cambodia
7 UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), Geneva, Switzerland
8 Department of Ambulatory Care and Community Medicine & Division of Infectious Diseases, University Hospital, Lausanne, Switzerland
Malaria Journal 2013, 12:235 doi:10.1186/1475-2875-12-235Published: 10 July 2013
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.