Objective: In 2020, FDA granted selumetinib (SEL) first approval for neurofibromatosis type 1 (NF1) with symptomatic, inoperable plexiform neurofibromas (PN) in paediatrics, with 25 mg/m² BSA as the initial dose, based on SPRINT study (NCT01362803). The purpose of this research was to simulate SEL exposure in Japanese paediatric population to establish a rationale to select 25 mg/m² in Japan paediatric study (D1346C00013) despite ethnic PK difference in healthy adults, with 51% higher AUC in Japanese than White, which is not fully explained by body-size difference alone [1].
Methods: Steady-state exposures of SEL and its metabolite at 25mg/m² in 1000 virtual Japanese or White patients from 3 to 18 years were simulated using a population PK model of SEL, having ethnicity, age and BSA as covariates [2]. Ethnic comparison was carried out using boxplot of C_max and AUC across age for discussing an acceptability of 25mg/m² dose in Japanese paediatrics. For the posteriori check of the simulation performance, the observations in Study D1346C00013 were overlayed on the boxplots of simulated data.
Results and Discussions: In the simulation, median AUC of SEL in Japanese was about 25% higher than White, with highly overlapping distributions. No significant ethnic difference was expected in AUC for the metabolite and C_max for both parent and metabolite. Since no clear exposure-response relationship for efficacy and safety was reported in the previous analysis [2], 25mg/m² was expected as an optimal dose in Japanese paediatrics. The exposures observed in Study D1346C00013 were within the 90% prediction intervals in Japanese population.
Conclusion: A population PK model developed using global paediatric and adult data accurately predicted the observed exposure in Japanese paediatric patients.
References:
1. Dymond AW et al. Eur J Clin Pharmacol. 2017;73:717-26
2. Schalkwijk S et al. Cancer Chemother Pharmacol. 2021;88(2):189-202