Pharmacokinetics of artemether-lumefantrine and artesunate-amodiaquine in children in Kampala, Uganda

Abstract

The World Health Organization recommends the use of artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria. The two most widely adopted ACT regimens are artemether (AR)-lumefantrine (LR) (the combination is abbreviated AL) and amodiaquine (AQ)-artesunate (AS). Pharmacokinetic (PK) data informing the optimum dosing of these drug regimens is limited, especially in children. We evaluated PK parameters in Ugandan children aged 5 to 13 years with uncomplicated malaria treated with AL (n = 20) or AQ-AS (n = 21), with intensive venous sampling occurring at 0, 2, 4, 8, 24, and 120 h following administration of the last dose of 3-day regimens of AL (twice daily) or AQ-AS (once daily). AS achieved an estimated maximum concentration in plasma (C(max)) of 51 ng/ml and an area under the concentration-time curve from time zero to infinity (AUC(0-infinity)) of 113 ng.h/ml; and its active metabolite, dihydroartemisinin (DHA), achieved a geometric mean C(max) of 473 ng/ml and an AUC(0-infinity) of 1,404 ng.h/ml. AR-DHA exhibited a C(max) of 34/119 ng/ml and an AUC(0-infinity) of 168/382 ng.h/ml, respectively. For LR, C(max) and AUC(0-infinity) were 6,757 ng/ml and 210 microg.h/ml, respectively. For AQ and its active metabolite, desethylamodiaquine (DEAQ), the C(max)s were 5.2 ng/ml and 235 ng/ml, respectively, and the AUC(0-infinity)s were 39.3 ng.h/ml and 148 microg.h/ml, respectively. Comparison of the findings of the present study to previously published data for adults suggests that the level of exposure to LR is lower in children than in adults and that the level of AQ-DEAQ exposure is similar in children and adults. For the artemisinin derivatives, differences between children and adults were variable and drug specific. The PK results generated for children must be considered to optimize the dosing strategies for these widely utilized ACT regimens.

FIG. 1.

PK dosing and sampling scheme for ACT regimens. The dosing times and PK sampling schedules are depicted for the AQ-AS and AL regimens. All doses were administered with food and fat. The drug levels in venous plasma were measured.

FIG. 2.

Mean ± standard deviation plasma concentration-versus-time profile after administration of the last dose for the longer-acting partner drugs. Profiles are depicted for the principle metabolite, DEAQ, and LR. The concentrations are displayed on logarithmic scales. *, for AL, due to the scheduling of the dosing to allow for administration of the last dose in the morning, the sample collection designed for 120 h after administration of the last dose occurred on day 8.

FIG. 3.

Scatterplot showing the correlation of the levels on day 7 with the AUC_0-∞s for both DEAQ and LR (for DEAQ on day 7, r_s = 0.97; for LR on day 7, r_s = 0.85; P < 0.0001 for all correlations). Dotted lines represent 95% CIs.

FIG. 4.

Relationship between exposure and weight-based dose adjustment for AL in children. The graph depicts the correlation of the AUC_0-∞ and the LR dosage (in mg/kg) in children.

FIG. 5.

The level of LR exposure is lower in African children with uncomplicated malaria than in healthy American adults. The graph depicts the distribution of AUC_0-∞ values for LR in children (n = 20) obtained in the current study and data for healthy adults (n = 10) obtained in a previous study (14). The dosing and sampling strategies were identical between the two studies.