Population Pharmacokinetic Properties of Sulfadoxine and Pyrimethamine: a Pooled Analysis To Inform Optimal Dosing in African Children with Uncomplicated Malaria

Antimicrobial Agents and Chemotherapy
M de KockPaolo Denti

Abstract

Sulfadoxine-pyrimethamine with amodiaquine is recommended by the World Health Organization as seasonal malaria chemoprevention for children aged 3 to 59 months in the sub-Sahel regions of Africa. Suboptimal dosing in children may lead to treatment failure and increased resistance. Pooled individual patient data from four previously published trials on the pharmacokinetics of sulfadoxine and pyrimethamine in 415 pediatric and 386 adult patients were analyzed using nonlinear mixed-effects modeling to evaluate the current dosing regimen and, if needed, to propose an optimized dosing regimen for children under 5 years of age. The population pharmacokinetics of sulfadoxine and pyrimethamine were both best described by a one-compartment disposition model with first-order absorption and elimination. Body weight, age, and nutritional status (measured as the weight-for-age Z-score) were found to be significant covariates. Allometric scaling with total body weight and the maturation of clearance in children by postgestational age improved the model fit. Underweight-for-age children were found to have 15.3% and 26.7% lower bioavailabilities of sulfadoxine and pyrimethamine, respectively, for each Z-score unit below -2. Under current dosin...Continue Reading

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Citations

May 23, 2018·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Anthony J Garcia-PratsH Simon Schaaf
Feb 13, 2019·Journal of Paediatrics and Child Health·Julie HuynhPhilip N Britton
Feb 26, 2020·Food and Waterborne Parasitology·Neda KonstantinovicFlorence Robert-Gangneux
Jul 13, 2021·Frontiers in Genetics·Alexandra T RouxMoses Okpeku

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