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

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

doi:10.1128/aac.02223-20

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.).

Highlights

When severe malaria is suspected in children, the WHO recommends pretreatment with a single rectal dose of artesunate before referral to an appropriate facility
The latter was retrospectively evaluated as having not met study inclusion criteria, as the child had received a full treatment of artemether-lumefantrine and an unidentified traditional medicine before coming to the hospital, but the information was disclosed to the staff only after enrollment
Children were brought to the center mainly because of fever (82/82, 100.0%; mean fever duration, 3.7 days; 95% confidence intervals (CI), 3.4 to 4.1), severe prostration (64/82, 78.0%; mean duration, 1.6 days; 95% CI, 1.4 to 1.8), and convulsions (7/82, 8.5%)

Summary

Introduction

When severe malaria is suspected in children, the WHO recommends pretreatment with a single rectal dose of artesunate before referral to an appropriate facility. Many children with severe malaria die before or just after reaching a facility capable of administering parenteral drugs. To address this need, a rectal formulation of artesunate has been developed that has been shown in very large communitybased trials to reduce malaria mortality in children unable to tolerate oral medications reliably [4,5,6,7,8,9,10]. In young children in Africa and Asia, rectal artesunate was associated with a reduced risk (RR) of death compared

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