Population pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant women with uncomplicated Plasmodium falciparum malaria in Burkina Faso: an open label trial

Abstract

Background: Malaria during pregnancy is a major health risk for both the mother and the foetus. Pregnancy has been shown to influence the pharmacokinetics of a number of different antimalarial drugs. This might lead to an under-exposure in these patients which could increase the risk of treatment failure and the development of drug resistance. The study aim was to evaluate the pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant patients using a population modelling approach. Methods: Twenty-four women in their second and third trimester of pregnancy and twenty-four paired non-pregnant women, all with uncomplicated P. falciparum malaria, were enrolled in this study. Treatment was a fixed-dose combination of oral artesunate and mefloquine once daily for three days. Frequent blood samples were collected and concentration-time data for artesunate and dihydroartemisinin were analysed simultaneously using nonlinear mixed-effects modelling. Results: Artesunate pharmacokinetics was best described by a transit-compartment absorption model followed by a one-compartment disposition model under the assumption of complete in vivo conversion of artesunate into dihydroartemisinin. Dihydroartemisinin pharmacokinetics was best described by a one-compartment disposition model with first-order elimination. Pregnant women had a 21% higher elimination clearance of dihydroartemisinin, compared to non-pregnant women, resulting in proportionally lower drug exposure. In addition, initial parasitaemia and liver status (alanine aminotransferase) were found to affect the relative bioavailability of artesunate. Conclusions: Results presented here show a substantially lower drug exposure to the antimalarial drug dihydroartemisinin during pregnancy after standard oral treatment of artesunate and mefloquine. This might result in an increased risk of treatment failure and drug resistance development, especially in low transmission settings where relative immunity is lower. Trial registration: ClinicalTrials.gov NCT00701961 (19/06/2008).

Keywords: Artemisinin-based combination therapy; Artesunate; Dihydroartemisinin; Malaria; Mefloquine; NONMEM; Population pharmacokinetics; Pregnancy.

Conflict of interest statement

No competing interests were disclosed.

Copyright: © 2019 Birgersson S et al.

Figures

Figure 1.. Structural representation of the final population pharmacokinetic model.

ARS is artesunate;DHA is dihydroartemisinin;k TR is the absorption rate constant;CL/F is the apparent elimination clearance;V/F is the apparent volume of distribution;F is the relative bioavailability of artesunate.

Figure 2.. Prediction-corrected visual predictive check of the final population pharmacokinetic model.

Predictive performance of the final population pharmacokinetic model of artesunate (A) and dihydroartemisinin (B) in pregnant and non-pregnant women. Open circles (upper panel) represent the observed concentrations and the solid lines represent the 5 th, 50 th and 95 th percentiles of the observed concentrations. Shaded areas show the 95% confidence interval of the 5 th, 50 th and 95 th percentiles of simulated concentrations. Solid black lines (lower panel) represent the observed fraction of data below the lower limit of quantification and the shaded area represents the 95% confidence intervals of simulated data below the lower limit of quantification for artesunate (C) and dihydroartemisinin (D).

Figure 3.. The impact of pregnancy on primary pharmacokinetic parameters.

Box and whisker plot of the results from the full covariate model investigating pregnancy as a categorical covariate. Boxes represent the 25 th to 75 th percentiles and whiskers represent the 10 th to 90 th percentiles. The solid vertical line represents no covariate effect and the dashed vertical lines represent a covariate effect of ±20%, which is assumed to be associated with clinical significance.F is the relative oral bioavailability,CL ARS/F is the apparent elimination clearance of artesunate,CL DHA/F is the apparent elimination clearance of dihydroartemisinin, andMTT is the mean absorption transit time. The covariate was added as a categorical function and bootstrapped (n=500).

Figure 4.. Goodness-of-fit diagnostics of the final population pharmacokinetic model for artesunate.

Descriptive performance of the final population pharmacokinetic model in pregnant and non-pregnant women. Lines represent weighted least-squares regression (dashed) and lines of identity (solid).

Figure 5.. Goodness-of-fit diagnostics of the final population pharmacokinetic model for dihydroartemisinin.

Descriptive performance of the final population pharmacokinetic model in pregnant and non-pregnant women. Lines represent weighted least-squares regression (dashed) and lines of identity (solid).

Figure 6.. The impact of pregnancy on secondary pharmacokinetic parameters.

Relative effect of pregnancy on simulated exposure (AUC and C MAX) to artesunate and dihydroartemisinin. The final model was used to simulate 1,000 non-pregnant and pregnant woman after an oral single dose of artesunate. All individual exposure parameters were divided on the average value for a non-pregnant women, to generate relative pregnancy effects. Boxes represent the 25 th to 75 th percentiles and whiskers represent the 10 th to 90 th percentiles. The vertical black line represents no covariate effect and the dashed vertical lines represent a covariate effect of ±20%, which is assumed to be associated with clinical significance.