Population Pharmacokinetic properties of Sulfadoxine and Pyrimethamine: A pooled analysis to Inform Optimal Dosing in African Children with Uncomplicated Malaria. [PublishAheadOfPrint]

Sulfadoxine/pyrimethamine with amodiaquine is recommended by the World Health Organization as seasonal malaria chemoprevention for children between 3 to 59 months in the sub-Sahel regions of Africa. Sub-optimal 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 paediatric and 386 adult patients were analysed using nonlinear mixed effects modelling to evaluate the current dosing regimen and, if needed, propose an optimised dosing regimen in children under five years old. 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 nutrition status (measured as weight-for-age z-scores) were found to be significant covariates. Allometric scaling with total body weight and maturation of clearance in children using post-gestational age improved the model fit. Underweight-for-age children were found to have 15.3% and 26.7% lower bioavailability of sulfadoxine and pyrimethamine, respectively, for each z-score unit below minus 2. Under current dosing recommendations, simulation predicted that the median day 7 concentration was below the 25^th percentile of a typical adult patient (50 kg) for sulfadoxine for patients in 8-9, 19-24, 46-49 and 74-79 kg weight bands, and for pyrimethamine for the weight-bands 8-9, 14-24 and 42-49 kg. An evidence-based dosing regimen was constructed that would achieve sulfadoxine and pyrimethamine exposure in young children and underweight-for-age young children that was similar to that currently seen in a typical adult.

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