Population pharmacokinetics of selumetinib and its N-desmethyl metabolite focused on Japanese and non-Japanese paediatric patients with NF1 PN

抄録

Objective: Selumetinib, a potent and selective MEK1/2 inhibitor, is used to treat paediatric patients with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN). BSA-based doses were used in studies for paediatric NF1 patients, including Japan phase I study (D1346C00013) and overseas phase I/II study (D1532C00057; SPRINT [1]). In healthy adults, selumetinib showed 51% higher dose normalized AUC in Japanese than White, partially explained by body size difference [2]. The objective of this PopPK analysis is to evaluate potential ethnic PK differences in paediatric patients after BSA-based dosing of selumetinib.

Methods: The analysis was conducted based on a previous model developed using data from healthy adults, adult malignancy patients and non-Japanese paediatric NF1 patients [3]. The analysis pooled D1346C00013 and SPRINT data including 80 PK evaluable patients (12 Japanese aged 7.5 to 18.2 years and 68 non-Japanese aged 3.0 to 18.5 years). Ethnic impact on PK was evaluated by: 1) covariate modelling including race (Japanese vs non-Japanese); 2) comparison of model-predicted exposure between Japanese and non-Japanese patients.

Results and Discussion: Final PopPK model parameters were estimated with reasonable precision (RSE<20%), and the estimates were consistent with the previous model [3]. Baseline BSA on CL, Vc of parent and CL of metabolite were statistically significant and important covariates with >20% impact. Predicted exposures showed overlapping distributions and consistent summary statistics between Japanese and non-Japanese.

Conclusion: Based on the analysis no ethnic difference in PK was detected, supporting appropriateness of using the same BSA-based dosing for both Japanese and non-Japanese paediatric NF1 patients.

References:

1. Gross AM et al. N Engl J Med. 2020;382(15):1430-42

2. Dymond AW et al. Eur J Clin Pharmacol. 2017;73:717-26

3. Schalkwijk S et al. Cancer Chemother Pharmacol. 2021;88(2):189-202