Severe Acute Malnutrition Results in Lower Lumefantrine Exposure in Children Treated With Artemether-Lumefantrine for Uncomplicated Malaria

Palang Chotsiri, Lise Denoeud-Ndam, Elisabeth Baudin, Ousmane Guindo, Halimatou Diawara, Oumar Attaher, Michiel Smit, Philippe J Guerin, Ogobara K Doumbo, Lubbe Wiesner, Karen I Barnes, Richard M Hoglund, Alassane Dicko, Jean-Francois Etard, Joel Tarning, Palang Chotsiri, Lise Denoeud-Ndam, Elisabeth Baudin, Ousmane Guindo, Halimatou Diawara, Oumar Attaher, Michiel Smit, Philippe J Guerin, Ogobara K Doumbo, Lubbe Wiesner, Karen I Barnes, Richard M Hoglund, Alassane Dicko, Jean-Francois Etard, Joel Tarning

Abstract

Severe acute malnutrition (SAM) has been reported to be associated with increased malaria morbidity in Sub-Saharan African children and may affect the pharmacology of antimalarial drugs. This population pharmacokinetic (PK)-pharmacodynamic study included 131 SAM and 266 non-SAM children administered artemether-lumefantrine twice daily for 3 days. Lumefantrine capillary plasma concentrations were adequately described by two transit-absorption compartments followed by two distribution compartments. Allometrically scaled body weight and an enzymatic maturation effect were included in the PK model. Mid-upper arm circumference was associated with decreased absorption of lumefantrine (25.4% decreased absorption per 1 cm reduction). Risk of recurrent malaria episodes (i.e., reinfection) were characterized by an interval-censored time-to-event model with a sigmoid maximum-effect model describing the effect of lumefantrine. SAM children were at risk of underexposure to lumefantrine and an increased risk of malaria reinfection compared with well-nourished children. Research on optimized regimens should be considered for malaria treatment in malnourished children.

Trial registration: ClinicalTrials.gov NCT01958905.

Conflict of interest statement

The authors declared no competing interests for this work.

© 2019 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Simulation‐based diagnostics for the final population pharmacokinetic model of lumefantrine. The top panel represents the prediction‐corrected visual predictive check. Open circles represent lumefantrine concentrations in severe acute malnutrition (SAM) children, and open triangles represent lumefantrine concentration in non‐SAM children. The solid line represents the 50th percentile of the observations, and the dashed lines represent the 5th and 95th percentiles of the observations. The gray areas represent the 95% confidence intervals of the simulated percentiles. The horizontal dashed line represents the lower limit of quantification (LLOQ) of lumefantrine (39.1 ng/mL). The bottom panel represents the visual predictive check of the data below the limit of quantification. The dashed line represents the observed proportion of LLOQ samples, and the shaded area represents the simulated 95% prediction interval of the proportion of LLOQ samples.
Figure 2
Figure 2
Effect of malnutrition descriptors on the pharmacokinetic (PK) parameters of lumefantrine. The graphs show the relative difference in PK parameter estimates in severe acute malnutrition (SAM) and non‐SAM children (a), and change in PK parameters estimates per 1‐cm mid‐upper arm circumferences reduction (b), and per 1 weight‐for‐age z‐score reduction (c). Y‐axes represent the change (%) in each PK parameter associated with altered malnutrition status, calculated from 1,000 bootstraps of the full covariate models. The shaded areas represent a covariate effect of ± 25%, assumed to be clinically insignificant. CL/F, oral clearance; F, relative bioavailability; MTT, mean transit time; QP/F, intercompartmental clearance; VC/F, apparent volume of distribution of the central compartment.
Figure 3
Figure 3
Simulation‐based diagnostics for the interval‐censoring time‐to‐event model of lumefantrine in severe acute malnutrition (SAM) and non‐SAM children. (a) Time‐to‐blood stage parasitemia and (b) time‐to‐malaria diagnostics. Black solid lines represent the observed Kaplan–Meier plots. Shaded areas represent the simulated 95% prediction intervals from the final pharmacodynamic model.
Figure 4
Figure 4
In silico lumefantrine dose optimization in severe acute malnutrition (SAM) and non‐SAM children. Predicted day 7 concentrations (a), area under the concentration‐time curve (AUC) (b), and maximum concentrations (Cmax) (c) of lumefantrine were plotted. Boxes and whiskers represent the median with interquartile range and the 95% prediction intervals, respectively. Horizontal dashed lines in panel a represent the median day 7 lumefantrine concentration after standard dosing regimen in nonpregnant adult patients (801 ng/mL).20 The dotted (200 ng/mL) and dashed‐dotted (175 ng/mL) lines in panel a represent the previously defined day 7 lumefantrine concentrations associated with therapeutic efficacy.21, 41 Gray areas in panel a represent the predicted clinical minimum inhibitory concentration value between 164 ng/mL and 182 ng/mL. Horizontal dashed lines in panels b and c represent the median lumefantrine exposure (AUC; 647,025 hour × ng/mL) and Cmax (6,731 ng/mL) after standard dosing in nonpregnant adult patients.20

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