Development of a physiologically based pharmacokinetic model for mefloquine and its application alongside a clinical effectiveness model to select an optimal dose for prevention of malaria in young Caucasian children.

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To predict the optimal chemoprophylactic dose of mefloquine in infants of 5-10kg using physiologically based pharmacokinetic (PBPK) and clinical effectiveness models. The PBPK model was developed in Simcyp version 14.1 and verified against clinical pharmacokinetic data in adults; the final model, accounting for developmental physiology and enzyme ontogeny was then applied in the paediatric population. The clinical effectiveness model utilized real-world chemoprophylaxis data with stratification of output by age and including infant data from the UK population. PBPK simulations in infant populations depend on the assumed fraction of mefloquine metabolized by CYP3A4 (0.47, 0.95) and on the associated CYP3A4 ontogeny (Salem, Upreti). However, all scenarios suggest that a dose of 62.5mg weekly achieves or exceeds the exposure in adults following a 250mg weekly dose and results in a minimum plasma concentration of 620ngml-1 , which is considered necessary to achieve 95% prophylactic efficacy. The clinical effectiveness model predicts a 96% protective efficacy from mefloquine chemoprophylaxis at 62.5mg weekly. The PBPK and clinical effectiveness models are mutually supportive and suggest a prophylactic dose of 62.5mg weekly in the Caucasian 5-10kg infant population travelling to endemic countries. This dual approach offers a novel route to dose selection in a vulnerable population, where clinical trials would be difficult to conduct.