Li, Ying Fei, Combes, Francois Pierre, Hoch, Matthias, Lorenzo, Sebastien, Sy, Sherwin and Ho, Yu-Yun (2022) Population pharmacokinetics of asciminib in tyrosine kinase inhibitor-treated patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic and acute phases. Clinical Pharmacokinetics, 61 (5). ISSN 0312-5963

Abstract

Background: Asciminib, a first-in-class highly potent BCR-ABL1 inhibitor has shown superior efficacy compared to the existing tyrosine kinase inhibitor TKI in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase, treated with ≥2 TKIs. This study aimed to describe pharmacokinetic properties of asciminib and to identify clinically relevant covariates impacting its exposure.

Methods: A population pharmacokinetics (PopPK) model was developed using a two-compartment model with delayed first-order absorption and elimination. The analysis included pharmacokinetics data from two clinical studies (Phases 1 and 3) involving 353 patients, with total daily asciminib doses range of 20-400 mg.
Results: The nominal total daily dose was incorporated as a structural covariate on clearance (CL), and body weight (BW) was included as a structural covariate via allometric scaling on CL and central volume. Renal function and formulation were included as statistically significant covariates on CL and absorption (ka), respectively. The simulation results revealed a modest but clinically non-significant effect of baseline BW and renal function on ka. Covariates such as baseline demographic and disease characteristics, hepatic function, and T315I mutation were not statistically significant and were not incorporated in the final model. Additionally, the final model-based simulations demonstrated comparable exposure and CL for asciminib 40 mg bid and 80 mg qd (an alternative regimen not studied in the Phase 3 trial), as well as similar PK properties in patients with and without T315I mutation.

Conclusions: The final PopPK model adequately characterized the pharmacokinetics properties of asciminib and assessed the impact of key covariates on its exposure. The model not only corroborates the use of the recommended asciminib dose of 40 mg bid, but also substantiates the use of 80 mg qd to facilitate patient’s compliance.

Item Type:	Article
Date Deposited:	13 Jul 2022 00:45
Last Modified:	13 Jul 2022 00:45
URI:	https://oak.novartis.com/id/eprint/46867