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

Abstract

Background: 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.

Methods: 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®).

Results: 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.

Conclusion: 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.

Figure 1

Study profiles. * Tanzania: hemoglobin <5.0 g/dL (2 patients), unable to swallow drug (1 patient), withdrawal of consent (2 patients), blood withdrawal not possible (1 patient), >9’999 parasites per 200 white blood cells (1 patient). Cambodia: withdrawal of consent (1 patient in each study). ** In 4 patients only DHA but no AS could be detected. *** Tanzania: 4 late clinical failures, 3 late parasitological failures and 1 late clinical and parasitological failure. Cambodia: 3 late parasitological failures in Phnom Dék and 1 late clinical failure in Pramoy. AM: artemether; AS: artesunate; DHA: dihydroartemisinin; LF: lumefantrine; MQ: mefloquine; PPQ: piperaquine.

Figure 2

Models used to describe AM, LF, MQ and PPQ and active metabolites DHA and DLF. For AM and LF, CL = (k₂₀– k₂₃) × V_C, with k₂₀ = CL/V_C. Because of problems of identification of k₂₃, V_M and CL_met, V_M was assumed to equal V_C. The concentration at baseline (C₀) was fitted by using a dummy dose of 1 mg times the estimated parameter F₀ (see text). AM: artemether; AS: artesunate; DHA: dihydroartemisinin; DLF: desbutyl-lumefantrine; LF: lumefantrine; MQ: mefloquine; PPQ: piperaquine.

Figure 3

Observed plasma concentrations of artemether (left panels) and dihydroartemisinin (right panels) after administration of 6 × 20 = 120 mg (children) and 6 × 80 = 480 mg (adults) artemether in 135 Tanzanian patients. The solid lines represent the mean population prediction and the dotted lines 95% prediction intervals. Triangles and squares represent residual plasma concentrations of lumefantrine and desbutyl-lumefantrine found prior treatment initiation.

Figure 4

Observed plasma concentrations of lumefantrine (left panels) and desbutyl-lumefantrine (right panels) after administration of 6 × 120 = 720 mg (children) and 6 × 480 = 2880 mg (adults) lumefantrine in 135 Tanzanian patients. The solid lines represent the mean population prediction and the dotted lines 95% prediction intervals. Triangles and squares represent residual plasma concentrations of lumefantrine and desbutyl-lumefantrine found prior treatment initiation.

Figure 5

Observed mefloquine plasma concentration after administration of a 2 × 125 = 250 mg (children) and 3 × 500 = 1500 mg (adults) dose in 63 Cambodian patients. The solid lines represent the mean population prediction the dotted lines the 95% prediction intervals. Triangles represent residual plasma concentrations of mefloquine or piperaquine found prior treatment initiation.

Figure 6

Observed piperaquine plasma concentrations after administration of 2 × 480 + 320 = 1280 mg (children) and 2 × 960 + 640 = 2560 mg (adults) dose in 60 Cambodian patients. The solid lines represent the mean population prediction the dotted lines the 95% prediction intervals. Triangles represent residual plasma concentrations of mefloquine or piperaquine found prior treatment initiation.

Figure 7

Concentration-time simulations of lumefantrine. A: Predicted median concentration of lumefantrine after administration of 6 × 480 mg (adults) regimen over 3 (continuous line) and 5 days (dotted line). Day 7 (168 h) median predicted concentrations (circles) with their 95% prediction intervals are shown for the two dosage regimens. B: Predicted mean (95% C.I.) time (estimated from time of last dose to 168 h) at which concentrations lie below the cut-off values of 50 ng/ml (rhombi), 175 ng/ml (triangles) and 280 ng/ml (squares). Full and empty symbols associated with continuous and dotted lines represent 6-dose regimens over 3 and 5 days respectively.