When severe malaria is suspected in children, WHO recommends pre-treatment with a single rectal dose of artesunate before referral to an appropriate facility. This was an individually randomized, open-label, 2-arm, cross-over clinical trial in 83 Congolese children with severe falciparum malaria, to characterize the pharmacokinetics of rectal artesunate. At admission, children received a single dose of rectal artesunate (10 mg/kg) followed 12 hours later by intravenous artesunate (2.4 mg/kg) or the reverse order. All children also received standard doses of intravenous quinine. Artesunate and dihydroartemisinin were measured at eleven fixed intervals, following 0- and 12-hour drug administrations. Clinical, laboratory and parasitological parameters were measured. After rectal artesunate, artesunate and dihydroartemisinin showed large inter-individual variability (peak concentrations of dihydroartemisinin ranged from 5.63 to 8,090 nM). The majority of patients however, reached previously suggested in vivo IC50 (98.7%) and IC90 (92.5%) values of combined concentrations of artesunate and dihydroartemisinin between 15 to 30 minutes after drug administration. The median (IQR) time above IC50 and IC90 was 5.68 hours (2.90-6.08) and 2.74 hours (1.52-3.75), respectively. The absolute rectal bioavailability (IQR) was 25.6% (11.7-54.5) for artesunate and 19.8% (10.3-35.3) for dihydroartemisinin. The initial 12-hour parasite reduction ratio was comparable between rectal and intravenous artesunate: median (IQR) 84.3% (50.0-95.4) vs. 69.2% (45.7-93.6), respectively (p=0.49). Despite large inter-individual variability, rectal artesunate can initiate and sustain rapid parasiticidal activity in most children with severe falciparum malaria, while they are transferred to a facility where parenteral artesunate is available. (www.clinicalTrials.gov : NCT02492178)
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