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Population pharmacokinetics of the antimalarial amodiaquine: a pooled analysis to optimize dosing

Ali, Ali Mohamed and Penny, Melissa A. and Smith, Thomas A. and Workman, Lesley and Sasi, Philip and Adjei, George O. and Aweeka, Francesca and Kiechel, Jean-René and Jullien, Vincent and Rijken, Marcus J. and McGready, Rose and Mwesigwa, Julia and Kristensen, Kim and Stepniewska, Kasia and Tarning, Joel and Barnes, Karen I. and Denti, Paolo and Wwarn Amodiaquine PK Study Group, . (2018) Population pharmacokinetics of the antimalarial amodiaquine: a pooled analysis to optimize dosing. Antimicrobial agents and chemotherapy, 62 (10). e02193-17.

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Abstract

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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Epidemiology and Public Health (EPH) > Infectious Disease Modelling > Disease and Intervention Dynamics (Penny)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Epidemiology and Public Health (EPH) > Infectious Disease Modelling > Infectious Disease Modelling (Smith)
UniBasel Contributors:Ali, Ali Mohamed and Penny, Melissa and Smith, Thomas A.
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society for Microbiology
ISSN:0066-4804
e-ISSN:1098-6596
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:16 Oct 2018 15:34
Deposited On:16 Oct 2018 15:33

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