A randomised controlled trial of 3 versus 5 days artemether-lumefantrine regimen for uncomplicated Plasmodium falciparum treatment in pregnancy in Africa

Artemether-lumefantrine antimalarial efficacy in pregnancy could be compromised by reduced drug exposure. Population-based simulations suggested that therapeutic efficacy would be improved if the treatment duration was increased. We assessed the efficacy, tolerability and pharmacokinetics of an extended 5-day regimen of artemether-lumefantrine compared to the standard 3-day treatment in 48 pregnant women and 48 non-pregnant women with uncomplicated falciparum malaria in an open-label, randomized clinical trial. Babies were assessed at birth, 1, 3, 6 and 12 months. Nonlinear mixed-effects modelling was used to characterise the plasma concentration-time profiles of artemether and lumefantrine and their metabolites. Both regimens were highly efficacious (100% PCR-corrected cure rates) and well tolerated. Babies followed up to 1 year had normal development. Parasite clearance half-lives were longer in pregnant women (median [range]: 3.30 [1.39-7.83] hours) compared to non-pregnant women (2.43 [1.05-6.00] hours), p=0.005. Pregnant women had lower exposures to artemether and dihydroartemisinin compared to non-pregnant women, resulting in 1.2% decreased exposure for each additional week of gestational age. By term, these exposures were reduced by 48% compared to non-pregnant patients. The overall exposure to lumefantrine was improved with the extended regimen, with no significant differences in exposures to lumefantrine or desbutyl-lumefantrine between pregnant and non-pregnant women. The extended artemether-lumefantrine regimen was well tolerated and safe and increased the overall antimalarial drug exposure, and so could be a promising treatment option in pregnancy in areas with lower malaria transmission and/or emerging drug resistance (http://www.clinicalTrials.gov/;NCT01916954)

Pharmacokinetic study of rectal artesunate in children with severe malaria in Africa

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

A randomised controlled trial of 3 versus 5 days artemether-lumefantrine regimen for uncomplicated Plasmodium falciparum treatment in pregnancy in Africa

Artemether-lumefantrine antimalarial efficacy in pregnancy could be compromised by reduced drug exposure. Population-based simulations suggested that therapeutic efficacy would be improved if the treatment duration was increased. We assessed the efficacy, tolerability and pharmacokinetics of an extended 5-day regimen of artemether-lumefantrine compared to the standard 3-day treatment in 48 pregnant women and 48 non-pregnant women with uncomplicated falciparum malaria in an open-label, randomized clinical trial. Babies were assessed at birth, 1, 3, 6 and 12 months. Nonlinear mixed-effects modelling was used to characterise the plasma concentration-time profiles of artemether and lumefantrine and their metabolites. Both regimens were highly efficacious (100% PCR-corrected cure rates) and well tolerated. Babies followed up to 1 year had normal development. Parasite clearance half-lives were longer in pregnant women (median [range]: 3.30 [1.39-7.83] hours) compared to non-pregnant women (2.43 [1.05-6.00] hours), p=0.005. Pregnant women had lower exposures to artemether and dihydroartemisinin compared to non-pregnant women, resulting in 1.2% decreased exposure for each additional week of gestational age. By term, these exposures were reduced by 48% compared to non-pregnant patients. The overall exposure to lumefantrine was improved with the extended regimen, with no significant differences in exposures to lumefantrine or desbutyl-lumefantrine between pregnant and non-pregnant women. The extended artemether-lumefantrine regimen was well tolerated and safe and increased the overall antimalarial drug exposure, and so could be a promising treatment option in pregnancy in areas with lower malaria transmission and/or emerging drug resistance (http://www.clinicalTrials.gov/;NCT01916954)