Increased systemic exposures of artemether and dihydroartemisinin in infants under 5 kg with uncomplicated Plasmodium falciparum malaria treated with artemether-lumefantrine (Coartem®)

Abstract

Background: Artemether-lumefantrine (AL) dispersible formulation was developed for the treatment of uncomplicated Plasmodium falciparum malaria in infants and children weighing 5 to <35 kg. However, there are no clinical studies with artemisinin-based combination therapy in infants <5 kg.

Methods: This multicentre, open-label, single-arm study evaluated the efficacy, safety and pharmacokinetics of AL dispersible in infants aged >28 days and <5 kg of body weight, who were treated with one AL dispersible tablet (20 mg artemether/120 mg lumefantrine) given twice-daily for three days and followed up for six weeks (core follow-up) and at 12 months of age (long-term follow-up).

Results: A total of 20 patients were enrolled and completed the six-week core study follow-up. In the per protocol population, PCR-corrected cure rate at days 28 and 42 was 100% (95% CI: 79.4, 100). AL dispersible was well tolerated with reported adverse events of mild to moderate severity. Pharmacokinetic data showed that lumefantrine levels were similar, however, artemether and dihydroartemisinin levels were on average two- to three-fold greater than historical values in infants and children ≥5 kg.

Conclusions: A three-day regimen of AL dispersible formulation was efficacious and generally well tolerated in infants weighing <5 kg with uncomplicated P. falciparum malaria, but artemether and dihydroartemisinin exposures could not be supported by the preclinical safety margins for neurotoxicity. Hence, dosing recommendations cannot be made in infants <5 kg as implications for toxicity are unknown.

Trial registration: Clinicaltrials.gov NCT01619878.

Figures

Figure 1

Subject disposition.

Figure 2

Parasite clearance time following treatment with artemether-lumefantrine dispersible. AL, artemether-lumefantrine. Parasite clearance time was defined as the time from first dose until total and continued disappearance of asexual forms for at least a further 48 hours (based on central microscopy reading). Subjects withdrawn from the study or on rescue medication before parasite clearance or those without parasite clearance till day 7 were considered censored at the time of withdrawal/start of rescue medication/day 7, whichever occurred earlier.

Figure 3

Fever clearance time following treatment with artemether-lumefantrine dispersible. AL, artemether–lumefantrine. Fever clearance time was defined as the time from first dose until the axillary temperature decreased and remained below 37.5οC for at least a further 48 hours. Subjects who were withdrawn from the study or who received anti-malarial rescue medication, within seven days and before the clearance was achieved were considered censored at the time of withdrawal/start of rescue medication.

Figure 4

Comparison of artemether (a) and dihydroartemisinin (b) exposure in different age and body weight groups.