Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis

Abstract

Background: The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations.

Methods and findings: A search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment 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. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest 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 absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7.

Conclusions: Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment.

Fig 1. Patient data disposition.

PK, pharmacokinetic; WWARN, WorldWide antimalarial resistance Network.

Fig 2. Prediction-corrected visual predictive checks.

(A) Prediction-corrected visual predictive check of the lumefantrine population pharmacokinetic model, with the insert representing the first 15 hours after dose. (B and C) Prediction-corrected visual predictive check of the lumefantrine/desbutyl-lumefantrine drug-metabolite model stratified for lumefantrine (B) and desbutyl-lumefantrine (C). The inserts in (B) and (C) show the predictive performance during the first 110 hours after dose. Open circles represent observed plasma concentration data. The solid lines represent the 5th, 50th, and 95th percentiles of the observed data. The grey shaded areas represent the 95% confidence intervals of the simulated (n = 2,000) percentiles.

Fig 3. Body weight, pregnancy status, admission parasitaemia, and dosage effects on predicted day 7 venous plasma lumefantrine concentrations (n = 2,000).

Body weight (top left); pregnancy status (top right); admission parasitaemia (bottom left); dosage (bottom right). Boxes and whiskers represent 25%–75% and 2.5%–97.5% of the data, respectively. The grey solid, dashed, and dotted lines represent 596 ng/ml (median lumefantrine concentration at day 7 in non-pregnant adult patients after a standard treatment), 200 ng/ml [16], and 175 ng/ml [23], respectively. The dotted black line in the parasitaemia panel represents the mean of the simulated data (open grey circles).

Fig 4. Visual predictive check of the pharmacokinetic-pharmacodynamic time-to-event model.

The grey shaded area represents the 95% confidence interval of the simulated (n = 2,000) data. Solid and dashed black lines represent the Kaplan–Meier estimator and corresponding standard errors. Panels show all data (top left), African children <15 kg (top right), African children ≥15 kg and <25 kg (bottom left), and pregnant women from Southeast Asia (bottom right).

Fig 5. In silico dose optimisations using Monte Carlo simulations (n = 2,000) with the final lumefantrine pharmacokinetic model for the different populations consisting of children weighing <15 kg, 15–24 kg, and 25–34 kg; non-pregnant adults ≥35 kg; and pregnant women.

The left, middle, and right column represent the results after a standard, intensified, and extended dosing regimen, respectively. The boxes and whiskers represent 25%–75% and 2.5%–97.5% of the data, respectively. The horizontal dashed-dotted grey line in the upper panels represents the median lumefantrine concentration at day 7 after standard treatment in non-pregnant adult patients (801 ng/ml). The dashed and dotted grey horizontal lines in the upper panels represent previously defined lumefantrine day 7 target concentrations of 175 and 200 ng/ml [16,23]. The horizontal grey dashed lines in the middle and lower panels represent the median lumefantrine area under the curve (AUC) (647,025 h × ng/ml) and maximum concentration (C_MAX) (6,731 ng/ml) after standard treatment in a non-pregnant adult patient population.