Pharmacokinetic study of rectal artesunate in children with severe malaria in Africa
Fanello C., Hoglund RM., Lee SJ., Kayembe D., Ndjowo P., Kabedi C., Badjanga BB., Niamyim P., Tarning J., Woodrow C., Gomes M., Day NP., White NJ., Onyamboko MA.
<jats:p>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 <jats:italic>falciparum</jats:italic> 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 <jats:italic>in vivo</jats:italic> IC<jats:sub>50</jats:sub> (98.7%) and IC<jats:sub>90</jats:sub> (92.5%) values of combined concentrations of artesunate and dihydroartemisinin between 15 to 30 minutes after drug administration. The median (IQR) time above IC<jats:sub>50</jats:sub> and IC<jats:sub>90</jats:sub> 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) <jats:italic>vs</jats:italic>. 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 <jats:italic>falciparum</jats:italic> malaria, while they are transferred to a facility where parenteral artesunate is available. (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.clinicalTrials.gov">www.clinicalTrials.gov</jats:ext-link> : NCT02492178)</jats:p>