Population Pharmacokinetics of Lumefantrine in Pregnant and Nonpregnant Women With Uncomplicated Plasmodium falciparum Malaria in Uganda

Abstract

Pregnancy alters the pharmacokinetic properties of many antimalarial compounds. The objective of this study was to evaluate the pharmacokinetic properties of lumefantrine in pregnant and nonpregnant women with uncomplicated Plasmodium falciparum malaria in Uganda after a standard fixed oral artemether-lumefantrine treatment. Dense venous (n = 26) and sparse capillary (n = 90) lumefantrine samples were drawn from pregnant patients. A total of 17 nonpregnant women contributed with dense venous lumefantrine samples. Lumefantrine pharmacokinetics was best described by a flexible absorption model with multiphasic disposition. Pregnancy and body temperature had a significant impact on the pharmacokinetic properties of lumefantrine. Simulations from the final model indicated 27% lower day 7 concentrations in pregnant women compared with nonpregnant women and a decreased median time of 0.92 and 0.42 days above previously defined critical concentration cutoff values (280 and 175 ng/ml, respectively). The standard artemether-lumefantrine dose regimen in P. falciparum malaria may need reevaluation in nonimmune pregnant women.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e83; doi:10.1038/psp.2013.59; advance online publication 13 November 2013.

Figure 1

Visual representation of the population pharmacokinetic lumefantrine model. CL/F, elimination clearance; K_TR, transit rate constant; Q/F, intercompartmental clearance; V_C/F, apparent central volume of distribution; V_P/F, apparent peripheral volume of distribution.

Figure 2

Box and whisker plot visualizing the effect of pregnancy on pharmacokinetic parameters from 200 bootstrap runs (boxes represent the 25–75% percentiles and whiskers represent the 2.5–97.5% percentiles of the bootstrap estimates). CL/F, elimination clearance; K_TR, transit rate constant; MTT, mean transit time; Q/F, intercompartmental clearance; V_C/F, apparent central volume of distribution; V_P/F, apparent peripheral volume of distribution.

Figure 3

Basic goodness-of-fit plots from the final lumefantrine model. The lines of identity are represented by the black solid lines and the trend lines (local polynomial regression fitting using 50 evaluations) are represented by the black dashed line.

Figure 4

Prediction-corrected visual predictive check of the final lumefantrine model for (a) all available data and when stratified for (b) pregnant women with capillary data, (c) pregnant women with venous data, and (d) nonpregnant women with venous data. Open circles represent the observed lumefantrine plasma concentrations. The 5th, 50th, and 95th percentiles of the observed data are represented by the solid black lines. The 95% confidence intervals of the 5th, 50th, and 95th percentiles of the 2,000 simulations are represented by gray-shaded areas.

Figure 5

An overview of the pregnancy effect on lumefantrine pharmacokinetics. (a) Population predicted concentration–time profiles of lumefantrine venous plasma concentrations in pregnant (black) and nonpregnant (gray) women based on 2,000 simulations from time 0 to day 14 and (b) zoomed in from day 8 to day 12. (c) Shows observed and individually predicted day 7 lumefantrine concentrations using the final population pharmacokinetic model. (d) Displays the simulated profiles for lumefantrine capillary plasma concentrations in Uganda (black) and Thailand (gray). Solid lines represent population means and dashed lines represent the 95th and 5th percentiles. The upper and lower horizontal dashed lines in a, b, and c represent the 280 and 175 ng/ml day 7 plasma concentration thresholds, respectively.