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-ؕ ) of 113 ng ⅐ h/ml; and its active metabolite, dihydroartemisinin (DHA), achieved a geometric mean C max of 473 ng/ml and an AUC 0-ؕ of 1,404 ng ⅐ h/ml. AR-DHA exhibited a C max of 34/119 ng/ml and an AUC 0-ؕ of 168/382 ng ⅐ h/ml, respectively. For LR, C max and AUC 0-ؕ were 6,757 ng/ml and 210 g ⅐ 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-ؕ s were 39.3 ng ⅐ h/ml and 148 g ⅐ 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.

Pharmacokinetic and Pharmacodynamic Characteristics of a New Pediatric Formulation of Artemether-Lumefantrine in African Children with Uncomplicated Plasmodium falciparum Malaria

“…In one study conducted in Ugandan children (26.5-kg body weight, on average), the geometric mean lumefantrine C max was 6.8 g/ml and the AUC from times zero to 120 h after the last dose amounted to 195 g ⅐ h/ml (19). The lower AUC compared to our analysis can be explained by different sample collection protocols.…”

“…These were 186 Ϯ 125 ng/ml for artemether and 101 Ϯ 58 ng/ml for DHA after the first dose of A-L (14). A recently published small study of children from Uganda assessed the pharmacokinetics of artemether and DHA after the third dose of an A-L tablet (19). The different study design limits the comparability of those pharmacokinetic results with the results of our analysis.…”

Pharmacokinetic Comparison of Two Piperaquine-Containing Artemisinin Combination Therapies in Papua New Guinean Children with Uncomplicated Malaria

“…This is supported by comparative pharmacokinetic studies in children and adults that found that children had a higher clearance (28) or a lower PQ exposure at critical times during the illness (44). These concerns have also been raised for other antimalarial drugs (8,33) and reflect pharmacokinetic effects due to the effects of body size, maturation, and organ function (3). Although only children aged between 5 and 10 years were included in the present study, we found that recurrence of parasitemia was associated with a lower PQ AUC resulting from a lower milligram/kilogram dose, consistent with other studies of DHA-PQ tetraphosphate (16).…”

“…Although the tolerability, safety, efficacy, and pharmacokinetics (PK) properties of DHA-PQ tetraphosphate have been widely investigated in children and adults (27,28,36,44,49), there are limited data relating to the efficacy and tolerability of 46) and no studies of the pharmacokinetics of this novel combination in malaria-infected patients. Concerns have been raised regarding possible underdosing in children for a number of antimalarial drugs (8,33), including PQ (27,36,49). Although children have been included in studies of PQ pharmacokinetics (28, 44), only one pharmacokinetic study of ART has specifically enrolled pediatric patients (40).…”

Functional Characterization of CYP2B6 Allelic Variants in Demethylation of Antimalarial Artemether

“…The conversion of AM to DHA is catalyzed by cytochrome P450 (P450) (van Agtmael et al, 1999b,c;Navaratnam et al, 2000). However, the elimination half-life of AM is very short, and it shows large interindividual variability in pharmacokinetic parameters (Na Bangchang et al, 1994;Mordi et al, 1997;van Agtmael et al, 1999a;Lefèvre et al, 2002;Ali et al, 2010;Mwesigwa et al, 2010).…”