Artesunate suppositories versus intramuscular artemether for treatment of severe malaria in children in Papua New Guinea

Abstract

Drug treatment of severe malaria must be rapidly effective. Suppositories may be valuable for childhood malaria when circumstances prevent oral or parenteral therapy. We compared artesunate suppositories (n = 41; 8 to 16 mg/kg of body weight at 0 and 12 h and then daily) with intramuscular (i.m.) artemether (n = 38; 3.2 mg/kg at 0 h and then 1.6 mg/kg daily) in an open-label, randomized trial with children with severe Plasmodium falciparum malaria in Papua New Guinea (PNG). Parasite density and temperature were measured every 6 h for > or = 72 h. Primary endpoints included times to 50% and 90% parasite clearance (PCT50 and PCT90) and the time to per os status. In a subset of 29 patients, plasma levels of artemether, artesunate, and their common active metabolite dihydroartemisinin were measured during the first 12 h. One suppository-treated patient with multiple complications died within 2 h of admission, but the remaining 78 recovered uneventfully. Compared to the artemether-treated children, those receiving artesunate suppositories had a significantly earlier mean PCT50 (9.1 versus 13.8 h; P = 0.008) and PCT90 (15.6 versus 20.4 h; P = 0.011). Mean time to per os status was similar for each group. Plasma concentrations of primary drug plus active metabolite were significantly higher in the artesunate suppository group at 2 h postdose. The earlier initial fall in parasitemia with artesunate is clinically advantageous and mirrors higher initial plasma concentrations of active drug/metabolite. In severely ill children with malaria in PNG, artesunate suppositories were at least as effective as i.m. artemether and may, therefore, be useful in settings where parenteral therapy cannot be given.

FIG. 1.

(A) Median (interquartile range) proportional reduction in parasite density following treatment with rectal artesunate or i.m. artemether. (B) Individual patient parasite density-time data (various symbols) from 41 children treated with rectal artesunate and (C) individual patient parasite density-time data (various symbols) from 38 children treated with i.m. artemether.

FIG. 2.

(A) Plasma artesunate and (B) dihydroartemisinin concentrations from 15 children following an 11-mg/kg dose of rectal artesunate. The closed circles are individual datum points, while the horizontal bars show median concentrations at the different times. The solid lines show simulated (using mean pharmacokinetic parameters) concentration-time profiles from our previous study of children with uncomplicated malaria (16).

FIG. 3.

(A) Plasma artemether and (B) dihydroartemisinin concentrations from 14 children following a 3.2-mg/kg dose of i.m. artemether. The closed circles are individual datum points, while the horizontal bars show median concentrations at the different times.