Pharmacometric evaluation of pre-referral rectal artesunate in children with severe malaria.

AIMS: Parenteral artesunate is the preferred first-line treatment for severe malaria. Pre-referral rectal artesunate suppositories are recommended where parenteral treatment is inaccessible. In this study, we compared dihydroartemisinin exposure and model-predicted early parasite clearance following rectal artesunate and intravenous artesunate in African children with severe malaria. METHODS: A total of 82 African children with severe malaria participated in a randomized crossover study in Democratic Republic of Congo. Forty children received rectal artesunate (10 mg/kg) while the other 42 received intravenous artesunate (2.4 mg/kg) as the first intervention, and then the other route of administration for the second dose. Blood samples were drawn for drug quantification, and nonlinear mixed-effects modelling was used to evaluate the pharmacokinetic properties of intravenous and rectal artesunate and to simulate expected parasite clearance associated with these routes of administration. RESULTS: The mean individually estimated rectal bioavailability of artesunate was 21% but was highly variable (IQR: 8%-35%). Plasma exposure to dihydroartemisinin-the principal and bioactive metabolite of artesunate-did not differ significantly between rectal and intravenous administration. Predicted parasite reduction over the first 12 h was similar for both routes, consistent with previously reported clinical benefits of rectal artesunate. CONCLUSIONS: These findings support the 10-mg/kg dose of rectal artesunate as a pre-referral intervention, which should be more widely deployed in malaria-endemic areas.