Disposition of Artesunate and Dihydroartemisinin after Administration of Artesunate Suppositories in Children from Papua New Guinea with Uncomplicated Malaria

Abstract

A detailed pharmacokinetic analysis was performed with 47 children from Papua New Guinea with uncomplicated falciparum or vivax malaria treated with artesunate (ARTS) suppositories (Rectocaps) given in two doses of approximately 13 mg/kg of body weight 12 h apart. Following an intensive sampling protocol, samples were assayed for ARTS and its primary active metabolite, dihydroartemisinin (DHA), by liquid chromatography-mass spectrometry. A population pharmacokinetic model was developed to describe the data. Following administration of the first dose, the mean maximal concentrations of ARTS and DHA were 1,085 nmol/liter at 0.9 h and 2,525 nmol/liter at 2.3 h, respectively. The absorption half-life for ARTS was 2.3 h, and the conversion half-life (ARTS to DHA) was 0.27 h, while the elimination half-life of DHA was 0.71 h. The mean common volumes of distribution for ARTS and DHA relative to bioavailability were 42.8 and 2.04 liters/kg, respectively, and the mean clearance values relative to bioavailability were 6 and 2.2 liters/h/kg for ARTS and DHA, respectively. Substantial interpatient variability was observed, and the bioavailability of the second dose relative to that of the first was estimated to be 0.72. The covariates age, sex, and ␣-thalassemia genotype were not influential in the pharmacokinetic model development; but the inclusion of weight as a covariate significantly improved the performance of the model. An ARTS suppositories dose of 10 of 20 mg/kg is appropriate for use in children with uncomplicated malaria.

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

“…Artemisinin drugs belong to a unique class of compounds; they are rapidly absorbed and eliminated, their peak concentrations in plasma occur in <30 min to 2 h after administration, and then decline rapidly [43][44][45]. Although it could be argued that these drugs are metabolized so rapidly that drug metabolism polymorphisms may not have pharmacological significance, a number of observations suggest otherwise.…”

Pharmacokinetics of a Novel Sublingual Spray Formulation of the Antimalarial Drug Artemether in African Children with Malaria

“…artemether administration in severely ill children (8). However, there is also marked between-patient variability in the dispositions of artesunate and DHA, and there is evidence that some children are able to expel artesunate suppositories even in the context of close monitoring as part of a formal pharmacokinetic evaluation (10). This might help explain why artesunate suppositories do not improve mortality compared to that with a placebo in older relative to younger pediatric age groups (11).…”

Artesunate Suppositories versus Intramuscular Artemether for Treatment of Severe Malaria in Children in Papua New Guinea

“…They have proved safe and efficacious for adults (3,20,22) and in small-scale studies of children with nonsevere infections from Africa (11,19), Southeast Asia (31), South America (10), and Papua New Guinea (PNG) (17). Their pharmacokinetic properties have been characterized previously (5,11,16,19), and maximal plasma drug concentrations, achieved within 1 to 2 h of administration of 10 to 20 mg/kg of body weight, are comparable to those when artesunate at 2 to 4 mg/kg is given by the oral, i.m., or i.v route (16,19). Although interindividual variability in rectal artesunate bioavailability is high, clinical response and tolerability are maintained over a wide plasma concentration range, consistent with the high therapeutic index of artemisinin drugs (16,19).…”

“…artemether for severe malaria in this setting. As an extension to a preliminary safety, efficacy, and pharmacokinetic evaluation (16,17), we have compared the efficacy of artesunate suppositories with that of i.m. artemether for treatment of severe pediatric malaria in PNG.…”