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Title: Population pharmacokinetics of the antimalarial amodiaquine: A pooled analysis to optimize dosing
Authors: Ali Mohamed Ali
Melissa A. Penny
Thomas A. Smith
Lesley Workman
Philip Sasi
George O. Adjei
Francesca Aweeka
Jean René Kiechel
Vincent Jullien
Marcus J. Rijken
Rose McGready
Julia Mwesigwa
Kim Kristensen
Kasia Stepniewska
Joel Tarning
Karen I. Barnes
Paolo Denti
Muhimbili University of Health and Allied Sciences
Ifakara Health Institute
Universite Paris Descartes
University of Oxford
University of California, San Francisco
Universitat Basel
Swiss Tropical and Public Health Institute (Swiss TPH)
University of Ghana
Universiteit Antwerpen
Mahidol University
Nuffield Department of Clinical Medicine
Novo Nordisk A/S
University of Cape Town
Medical Research Council Unit
Drugs for Neglected Diseases Initiative
Keywords: Medicine;Pharmacology, Toxicology and Pharmaceutics
Issue Date: 1-Oct-2018
Citation: Antimicrobial Agents and Chemotherapy. Vol.62, No.10 (2018)
Abstract: © 2018 Ali et al. Amodiaquine plus artesunate is the recommended antimalarial treatment in many countries where malaria is endemic. However, pediatric doses are largely based on a linear extrapolation from adult doses. We pooled data from previously published studies on the pharmacokinetics of amodiaquine, to optimize the dose across all age groups. Adults and children with uncomplicated malaria received daily weight-based doses of amodiaquine or artesunate-amodiaquine over 3 days. Plasma concentration-time profiles for both the parent drug and the metabolite were characterized using nonlinear mixed-effects modeling. Amodiaquine pharmacokinetics were adequately described by a two-compartment disposition model, with first-order elimination leading to the formation of desethylamodiaquine, which was best described by a three-compartment disposition model. Body size and age were the main covariates affecting amodiaquine clearance. After adjusting for the effect of weight, clearance rates for amodiaquine and desethylamodiaquine reached 50% of adult maturation at 2.8 months (95% confidence interval [CI], 1.5 to 3.7 months) and 3.9 months (95% CI, 2.6 to 5.3 months) after birth, assuming that the baby was born at term. Bioavailability was 22.4% (95% CI, 15.6 to 31.9%) lower at the start of treatment than during convalescence, which suggests a malaria disease effect. Neither the drug formulation nor the hemoglobin concentration had an effect on any pharmacokinetic parameters. Results from simulations showed that current manufacturer dosing recommendations resulted in low desethylamodiaquine exposure in patients weighing 8 kg, 15 to 17 kg, 33 to 35 kg, and >62 kg compared to that in a typical 50-kg patient. We propose possible optimized dosing regimens to achieve similar drug exposures among all age groups, which require further validation.
ISSN: 10986596
Appears in Collections:Scopus 2018

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