Pharmacokinetics of oral artesunate in children with moderately severe Plasmodium falciparum malaria

Abstract

The pharmacokinetic properties of oral artesunate (3 mg/kg) were determined in 10 Vietnamese children, aged from 6 to 15 years, with acute falciparum malaria of moderate severity. Plasma concentrations were measured using a bioassay and expressed in terms of antimalarial activity equivalent to dihydroartemisinin, the principal biologically active metabolite. Oral artesunate was absorbed rapidly with a mean time to peak plasma bioactivity of 1.7 h (95% confidence interval [95% CI] 0.8-2.6). There was wide variation in peak plasma concentrations with a mean value equivalent to 664 ng of dihydroartemisinin/mL (95% CI 387-9410, range 179-1395) and a four-fold variation in the area under the plasma concentration-time curves. Elimination from plasma was rapid with a mean (95% CI) half-life of 1.0 h (95% CI 0.8-1.4). Plasma antimalarial levels were below the limit of detection in all cases by 12 h, despite the relatively high dose of artesunate used. Oral artesunate is rapidly absorbed and rapidly eliminated in children with moderately severe malaria but there is considerable variation between individuals.

Assessment of the effect of malaria infection on hepatic clearance of dihydroartemisinin using rat liver perfusions and microsomes

“…The supposition that DHA is metabolized to inactive compounds has been supported by a recent study in which pharmacokinetic parameters for DHA were calculated from plasma concentration-time data that were obtained by bioassay (Bethell et al, 1997). The pharmacokinetic parameters were consistent with data reported from similar clinical studies using selective high performance liquid chromatography (h.p.l.c.)…”

Prevalence of UGT1A9 and UGT2B7 nonsynonymous single nucleotide polymorphisms in West African, Papua New Guinean, and North American populations

“…Large interindividual variations in the pharmacokinetics of DHA have also been seen in healthy Southeast Asian and Caucasian subjects [50][51][52][53]. The basis for such a large inter-individual pharmacokinetic variability observed in these studies [43,44,[46][47][48][49] may include drug metabolism polymorphisms. One explanation for these observations may center on the joint contribution of both cytochrome P450 2B6 (CYP2B6)and UGT2B7 polymorphisms.…”

“…Several studies, involving Southeast Asian, Papua New Guinean, and African malaria patients given artesunate or artemether, have reported large interindividual variations in the main pharmacokinetic parameter values of DHA, depending on the dose and route of administration. These include the area under the concentration-time curve (2-to 26-fold) [43,[46][47][48], the peak concentrations of DHA in plasma (2-to 54-fold) [43,44,[46][47][48], and the clearance/bioavailability for DHA (2-to 22-fold) [43,46,48,49]. Large interindividual variations in the pharmacokinetics of DHA have also been seen in healthy Southeast Asian and Caucasian subjects [50][51][52][53].…”

Artesunate versus artemether for the treatment of recrudescent multidrug-resistant falciparum malaria.

“…The maximum effect on parasite clearance with artesunate has been observed at a dose of 2 mg/kg (Angus BJ, White NJ, unpublished data), but these findings should be taken in context with the considerable interindividual variability in plasma concentration profiles following the oral administration of this drug. 15 Some patients receiving 2 mg/kg may therefore have had suboptimal (i.e., less than the minimum parasiticidal concentration) blood concentrations in the first day of treatment. Furthermore, artemether was give at a 28% higher dose in molar terms.…”