Pharmacokinetic Study of Rectal Artesunate in Children with Severe Malaria in Africa

Caterina Fanello, Richard M Hoglund, Sue J Lee, Daddy Kayembe, Pauline Ndjowo, Charlie Kabedi, Benjamin B Badjanga, Phettree Niamyim, Joel Tarning, Charles Woodrow, Melba Gomes, Nick P Day, Nicholas J White, Marie A Onyamboko, Caterina Fanello, Richard M Hoglund, Sue J Lee, Daddy Kayembe, Pauline Ndjowo, Charlie Kabedi, Benjamin B Badjanga, Phettree Niamyim, Joel Tarning, Charles Woodrow, Melba Gomes, Nick P Day, Nicholas J White, Marie A Onyamboko

Abstract

When severe malaria is suspected in children, the WHO recommends pretreatment with a single rectal dose of artesunate before referral to an appropriate facility. This was an individually randomized, open-label, 2-arm, crossover clinical trial in 82 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 of body weight) followed 12 h 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 11 fixed intervals, following 0- and 12-h drug administrations. Clinical, laboratory, and parasitological parameters were measured. After rectal artesunate, artesunate and dihydroartemisinin showed large interindividual variability (peak concentrations of dihydroartemisinin ranged from 5.63 to 8,090 nM). The majority of patients, however, reached previously suggested in vivo IC50 and IC90 values (98.7% and 92.5%, respectively) of combined concentrations of artesunate and dihydroartemisinin between 15 and 30 min after drug administration. The median (interquartile range [IQR]) time above IC50 and IC90 was 5.68 h (2.90 to 6.08) and 2.74 h (1.52 to 3.75), respectively. The absolute rectal bioavailability (IQR) was 25.6% (11.7 to 54.5) for artesunate and 19.8% (10.3 to 35.3) for dihydroartemisinin. The initial 12-h parasite reduction ratio was comparable between rectal and intravenous artesunate: median (IQR), 84.3% (50.0 to 95.4) versus 69.2% (45.7 to 93.6), respectively (P = 0.49). Despite large interindividual 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. (This study has been registered at ClinicalTrials.gov under identifier NCT02492178.).

Keywords: antimalarial agents.

Copyright © 2021 Fanello et al.

Figures

FIG 1
FIG 1
Flow chart CONSORT.
FIG 2
FIG 2
Observed individual artesunate concentration-time profiles. Artesunate and dihydroartemisinin were administered intravenously or rectally. The dashed horizontal line represents a putative IC50 value of 34.9 nM, and the dotted horizontal line represents a putative IC90 value of 314 nM. The red line represents the patient who did not reach the IC50 value after rectal administration.
FIG 3
FIG 3
Graphical representation of time to putative IC50 (T-IC50), time above IC50 (T>IC50), time to putative IC90 (T-IC90), and time above IC90 (T>IC90) after rectal artesunate administration. Concentrations were measured as the sum of molar artesunate and dihydroartemisinin concentrations. Markers represent individual values and lines represent the median value and its interquartile range. The graphic shows only data for patients who reached the cutoff (IC50 or IC90). One patient did not reach IC50. The red dots indicate the 2 cases with a longer time to reach IC90.

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