Kloprogge F, et al. - In view of the observation that the fixed-dose combination of artemether-lumefantrine (AL) (the most widely used treatment for uncomplicated Plasmodium falciparum malaria) results in relatively lower cure rates and lumefantrine levels in young children and in pregnant women during their second and third trimester, researchers sought for the optimal dosing regimens in all patient populations via investigating the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine. They developed a population pharmacokinetic-pharmacodynamic model for lumefantrine to understand how body weight, pregnancy, and baseline parasite density influence drug levels. For small children and pregnant women beyond their first trimester, a 5-day regimen of current weight-based standard twice-daily doses proved to be most favourable from a pharmacological perspective.

Methods

• Researchers performed a search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database.
• Thirty one relevant clinical studies published between 1 January 1990 and 31 December 2012 were identified.
• The studies comprised of 4,546 patients in whom lumefantrine concentrations were measured.
• Under the auspices of WWARN, they obtained relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients and pooled the data for the meta-analysis.

Results

• Through in silico simulations, they used the developed lumefantrine population pharmacokinetic model for dose optimisation.
• Seven days after starting standard AL treatment, venous plasma lumefantrine concentrations were 24.2% and 13.4% lower in children weighing <15 kg and 15–25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults.
• With increasing pre-treatment parasitaemia, lumefantrine exposure decreased, and the dose limitation on absorption of lumefantrine was substantial.
• Using the lumefantrine pharmacokinetic model, simulations suggested that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days).
• The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat.
• The prediction of parasite killing rates and recrudescent infections was limited due to the absence of artemether-dihydroartemisinin data.
• Thus, the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7 was suggested to underlie the optimised dosing schedule.