Development of a PBPK Model for Mefloquine and its Application alongside a Clinical Effectiveness Model to Select an Optimal Dose for Prevention of Malaria in Young Caucasian Children.

AIMS: To predict the optimal chemoprophylactic dose of mefloquine in infants of 5 to 10 kg using physiologically based pharmacokinetic (PBPK) and clinical effectiveness models.

METHODS: 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.

RESULTS: 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 plasma Cmin of 620ng/ml which is considered necessary to achieve 95% prophylactic efficacy. The clinical effectiveness model predicts a 96% protective efficacy from mefloquine chemoprophylaxis at 62.5 mg weekly.

CONCLUSIONS: The PBPK and clinical effectiveness models are mutually supportive and suggest a prophylactic dose of 62.5mg weekly in the Caucasian 5 to 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. What is already known about this subject? Mefloquine has an established role in the chemoprophylaxis of malaria in adults and children. The doses recommended for infants and young children 5 to 10kg vary between national guidelines from 32.25 to 62.5mg.

WHAT THIS STUDY ADDS: A PBPK model of mefloquine was developed and verified in adults and pharmacokinetics was predicted in a paediatric population accounting for model uncertainties. A clinical effectiveness model based on real world data was applied to predict the most likely effective dose in the same paediatric population. Both model approaches suggest a weekly prophylactic dose of 62.5mg in the. 5 to 10kg Caucasian population.