Publication: Population pharmacokinetics of the antimalarial amodiaquine: A pooled analysis to optimize dosing
Issued Date
2018-10-01
Resource Type
ISSN
10986596
00664804
00664804
Other identifier(s)
2-s2.0-85053909102
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Mahidol University
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SCOPUS
Bibliographic Citation
Antimicrobial Agents and Chemotherapy. Vol.62, No.10 (2018)
Suggested Citation
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 Population pharmacokinetics of the antimalarial amodiaquine: A pooled analysis to optimize dosing. Antimicrobial Agents and Chemotherapy. Vol.62, No.10 (2018). doi:10.1128/AAC.02193-17 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/46312
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Title
Population pharmacokinetics of the antimalarial amodiaquine: A pooled analysis to optimize dosing
Other Contributor(s)
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
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
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.