The impact of NR1I2 gene polymorphism and body weight on asciminib pharmacokinetics in patients with chronic myeloid leukemia

Abstract Introduction: Asciminib (ASC), the first STAMP inhibitor for chronic myeloid leukemia in chronic phase (CML-CP), has demonstrated superior efficacy and safety compared to traditional ABL TKIs in global trials. In Japan, the standard dosage of ASC has transitioned from 40 mg twice daily (BID) to 80 mg once daily (QD). While population pharmacokinetic (PK) models exist, real-world data in patients, direct comparisons of BID and QD regimens, and the influence of pharmacogenetic polymorphisms on ASC exposure are limited. Purpose: This study aimed to characterize the PK of asciminib in patients with CML, compare the PK and adherence between 40 mg BID and 80 mg QD regimens, and evaluate the effect of polymorphisms in key pharmacogenes (CYP3A4, UGT2B7, ABCB1, ABCG2, ABCC2, NR1I2, AHR) on asciminib plasma concentrations. Patients and Methods: Thirty-nine CML patients (12 female, 27 male) treated with asciminib at Akita University Hospital between April 2022 and July 2025 were enrolled. The study protocol was approved by the institutional ethics committee, and all patients provided written informed consent. Plasma concentrations of asciminib for both 40 mg BID and 80 mg QD regimens were measured at steady-state (C0, 1, 2, 4, and 12 or 24h post-dose) using high-performance liquid chromatography. Genotyping for PK-related polymorphisms was performed using PCR-RFLP. Results: The median AUC for the 40 mg BID and 80 mg QD regimens showed high inter-individual variability (CV: 50.4% and 34.2%, respectively). While total asciminib clearance was similar between the two regimens (p=0.404), the median AUC was significantly higher in female patients for both dosing schedules (p=0.009 and p=0.004, respectively). A significant correlation was observed between asciminib AUC and body weight for both regimens (p=0.042 and p<0.001, respectively). Notably, the asciminib AUC0-12 for the 40 mg BID regimen was significantly lower in patients carrying the NR1I2 -25385T allele compared to those with the C/C genotype (p=0.001). Multiple regression analysis identified the NR1I2 polymorphism (p=0.001) and female sex (p=0.002) as independent predictors for AUC in the 40 mg BID regimen, while body weight (p<0.001) and female sex (p=0.047) were predictors for the 80 mg QD regimen. Conclusions: The initial dose of asciminib may require adjustment based on NR1I2 genotype and patient body weight. As the 80 mg QD regimen is more influenced by body weight than by the tested genetic polymorphisms, underweight female patients treated with this regimen may exhibit higher drug exposure.