Population pharmacokinetics of lumefantrine in pregnant and non‐pregnant women with uncomplicated Plasmodium falciparum malaria in Western Kenya

Aim This study intends to assess the pharmacokinetic properties and treatment response of lumefantrine in pregnant and non‐pregnant women with uncomplicated Plasmodium falciparum malaria infection in Western Kenya. Methods Seventy‐five women with uncomplicated P . falciparum malaria were enrolled, including 25 non‐pregnant, 30 pregnant women in the second trimester and 20 pregnant women in their third trimester. The participants received a standard dose of artemether–lumefantrine (80/480 mg) twice daily for 3 days. Densely venous plasma samples were collected. Nonlinear mixed‐effects modelling was used to characterize the pharmacokinetic properties of lumefantrine, and the effects of pregnancy was assessed on all pharmacokinetic parameters by a full covariate modelling approach. Results The concentration‐time data of lumefantrine were described adequately by a two‐compartment disposition model, with a flexible transit absorption and first‐order elimination. Covariate modelling results demonstrated that pregnancy status or gestational age had a significant impact on both elimination clearance (CL) and the central volume of distribution (Vc) of lumefantrine. The estimated pregnancy effects on CL and Vc were 23% (95%CI: 10.8–34.8%) and 28% (95%CI: 7.3–51.8%), respectively. Pregnant women exhibited lower drug exposure compared to non‐pregnant women, with the geometric mean ratios (GMRs) of 0.76 (95% CI: 0.57–1.01), 0.79 (95% CI: 0.63–0.99) and 0.69 (95% CI: 0.51–0.94) for area under the concentration‐time curve (AUC), maxinum concentration ( C max ) and Day 7 concentration, respectively. Other covariates did not significantly affect the pharmacokinetics of lumefantrine. The 28‐day polymerase chain reaction (PCR)‐corrected parasitological cure was 100% for both pregnant and non‐pregnant women. Conclusions The exposure to lumefantrine was lower in pregnant women, compared to non‐pregnant women, with uncomplicated P. falciparum infection. This lower drug exposure might increase the risk of treatment failure with artemether–lumefantrine in pregnant women, especially if susceptibility to either drug is reduced. Continuous assessment and monitoring of the efficacy of artemether–lumefantrine in pregnant women are warranted.