Population Pharmacokinetic Analysis of Selumetinib and Its N-desmethyl Metabolite in Japanese and Non-Japanese Pediatric Patients with Neurofibromatosis Type 1 and Inoperable Plexiform Neurofibromas

Background. Selumetinib, a mitogen-activated protein kinase kinase 1/2 inhibitor, has been approved in several countries and regions, including Japan, for the treatment of pediatric patients with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas at a body surface area (BSA)-based dose of 25 mg/m² twice daily. The objective of this population pharmacokinetic analysis was to evaluate ethnic sensitivity in the pharmacokinetics of selumetinib and N-desmethyl selumetinib between Japanese and non-Japanese pediatric patients. Methods. This population pharmacokinetic analysis was based on data from 80 pediatric patients enrolled in two clinical trials, one conducted in Japan and one conducted in the United States, comprising 12 Japanese participants and 68 non-Japanese participants. Both clinical trials used BSA-based dosing schemes. A two-compartment model with first-order elimination and sequential zero-order and first-order delayed absorption for selumetinib, combined with a one-compartment model with first-order elimination for N-desmethyl selumetinib, was used for this analysis. Ethnic sensitivity in pharmacokinetics was evaluated by covariate modeling and comparison of model-predicted exposures. Results. Covariate modeling showed that BSA had a clinically relevant impact on the pharmacokinetics of selumetinib. None of the other investigated covariates, such as race, had a significant impact. The predicted exposure in Japanese and non-Japanese patients showed a considerably overlapping distribution, and no clinically relevant difference in exposure was apparent. Conclusions. These findings support the use of the same BSA-based dosing regimen for Japanese and non-Japanese pediatric patients with neurofibromatosis type 1 and inoperable plexiform neurofibromas. Subsequent to this analysis, selumetinib was approved at the BSA-based dose of 25 mg/m² in Japan, which is consistent with the recommended dosage and administration in other regions and countries. This analysis used data from trial registered with NCT04495127, and NCT01362803.