Optimizing Amodiaquine Dosing in Nigeria: A Population Pharmacokinetic Study to Inform Seasonal Malaria Chemoprevention

Abstract

<title>Abstract</title> Amodiaquine-containing antimalarial combinations have been shown to be effective for both malaria treatment and seasonal malaria chemoprevention in children under five years of age, particularly in high-burden regions such as Nigeria. This study developed a population pharmacokinetic model to describe amodiaquine disposition and simulate desethylamodiaquine concentrations, providing insights into optimizing its efficacy and safety in Seasonal Malaria chemoprevention. Two hundred and sixty-six plasma concentrations of amodiaquine were collected from 34 healthy volunteers across two pharmacokinetic studies where amodiaquine was administered. A population pharmacokinetic model was developed for amodiaquine via Monolix 2023R1 software. Nonparametric bootstrap analysis and model-based simulations for day 3, day 7, and day 28 and maximum concentrations of desethylamodiaquine were conducted with the R package. Amodiaquine was best described by a two-compartment model with two transit compartments, a mean transit time of 0.896 h, and a clearance of 2200 L/hr. The allometric scaling of weight on all the clearances and volumes of the distribution parameters significantly improved the model. The highest mean model-based simulation day 7 concentration for desethylamodiaquine was 138.27 ng/ml in adults and 104.96 ng/ml in pediatrics. This study highlights that desethylamodiaquine concentrations are higher than the efficacy thresholds, highlighting the suitability of amodiaquine's current dosing for seasonal malaria chemoprevention in Nigeria. These findings emphasize the need for further research in malaria patients to assess the influence of parasitaemia, genetics, and coadministered drugs, ultimately guiding the optimization of amodiaquine-containing regimens in the country.