Background: Inter-individual variability in plasma concentration-time profiles might contribute to differences in\r\nanti-malarial treatment response. This study investigated the pharmacokinetics of three different forms of\r\nartemisinin combination therapy (ACT) in Tanzania and Cambodia to quantify and identify potential sources of\r\nvariability.\r\nMethods: Drug concentrations were measured in 143 patients in Tanzania (artemether, dihydroartemisinin,\r\nlumefantrine and desbutyl-lumefantrine), and in 63 (artesunate, dihydroartemisinin and mefloquine) and 60\r\n(dihydroartemisinin and piperaquine) patients in Cambodia. Inter- and intra-individual variabilities in the\r\npharmacokinetic parameters were assessed and the contribution of demographic and other covariates was\r\nquantified using a nonlinear mixed-effects modelling approach (NONMEM�®).\r\nResults: A one-compartment model with first-order absorption from the gastrointestinal tract fitted the data for all\r\ndrugs except piperaquine (two-compartment). Inter-individual variability in concentration exposure was about 40%\r\nand 12% for mefloquine. From all the covariates tested, only body weight (for all antimalarials) and concomitant\r\ntreatment (for artemether only) showed a significant influence on these drugsâ�� pharmacokinetic profiles. Artesunate\r\nand dihydroartemisinin could not be studied in the Cambodian patients due to insufficient data-points. Modeled\r\nlumefantrine kinetics showed that the target day 7 concentrations may not be achieved in a substantial proportion\r\nof patients.\r\nConclusion: The marked variability in the disposition of different forms of ACT remained largely unexplained by the\r\navailable covariates. Dosing on body weight appears justified. The concomitance of unregulated drug use (residual\r\nlevels found on admission) and sub-optimal exposure (variability) could generate low plasma levels that contribute\r\nto selecting for drug-resistant parasites.
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