A randomised controlled trial of 3 versus 5 days artemether-lumefantrine regimen for uncomplicated Plasmodium falciparum treatment in pregnancy in Africa.
Onyamboko MA., Hoglund RM., Lee SJ., Kabedi C., Kayembe D., Badjanga BB., Turner GDH., Jackson NV., Tarning J., McGready R., Nosten F., White NJ., Day NPJ., Fanello C.
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).