Hoch, Matthias, Huth, Felix, Manley, Paul, Konstantinidis, Ioannis Loisios, Combes, Francois Pierre, Li, Ying Fei, Sy, Sherwin, Obourn, Vanessa, Chakraborty, Abhijit and Hourcade-Potelleret, Florence (2024) Clinical Pharmacology of Asciminib: A Systematic Review. Clinical pharmacokinetics.

Abstract

Asciminib is the first-in-class allosteric inhibitor of the kinase activity of BCR::ABL1, Specifically Targeting the ABL Myristoyl Pocket (STAMP). This review focuses on the pharmacokinetic (PK) and pharmacodynamic data of asciminib, which is approved for the treatment of adult patients with chronic myeloid leukemia in chronic phase (CML-CP) who are either resistant or intolerant to ≥2 alternative therapies (at a total daily dose of 80 mg), or those harboring the T315I mutation (at a dose of 200 mg twice-daily (b.i.d.).
Asciminib is predicted to be almost completely absorbed from the gut, with an absolute bioavailability (F) of approximately 73%. Asciminib displays a slightly greater than dose-proportional increase in exposure, and no time-dependent changes in PK have been observed following repeated dosing.
This drug shows low clearance (4.34 L/hr), with a moderate volume of distribution (111 L) and high human plasma protein binding (97.3%). The apparent terminal elimination half-life (T1/2) across studies was estimated to be between 7 and 15 hours. The PK of asciminib is not substantially affected by body weight, age, gender, race, or renal or hepatic impairment.
Asciminib is primarily metabolized via CYP3A4-mediated oxidation (36.0%) and UGT2B7- and UGT2B17-mediated glucuronidation (13.3% and 7.8%, respectively); biliary secretion via breast cancer resistance protein (BCRP) contributes to about 31.1% to total systemic clearance, which is mainly through hepatic metabolism and biliary secretion through the fecal pathway, with renal excretion playing a minor role.
Potential for pharmacokinetic drug interaction for asciminib both as a victim as well as a perpetrator have been summarized here based on clinical and predicted drug-drug interaction studies.
Administration of asciminib with food reduced exposure compared to administration in the fasted state; the observed decrease was more substantial with high-fat meals.
Robust exposure-response models characterized asciminib exposure-efficacy and exposure-safety relationships. In patients without the T315I mutation, the exposure-efficacy analysis of the time course of BCR::ABL1IS percentages highlighted the existence of a slightly positive, albeit not clinically significant, relationship. Higher exposure was required for efficacy in patients harboring the T315I mutation compared to those who did not. The exposure-safety relationship analysis showed no apparent association between exposure and adverse events of interest over the broad range of exposure or dose levels investigated. Asciminib has also been shown to have no clinically relevant effect on cardiac repolarization.
Here, we review the clinical pharmacology data available to date for asciminib that supported its clinical development program and regulatory applications.

Item Type:	Article
Date Deposited:	13 Nov 2024 00:45
Last Modified:	13 Nov 2024 00:45
URI:	https://oak.novartis.com/id/eprint/52490