Disposition of asciminib, a potent BCR-ABL1 tyrosine kinase inhibitor, in healthy male subjects
Creators: name: Tran, Phi
name: Hanna, Imad
name: Eggimann, Fabian Kurt
name: Schoepfer, Joseph
name: Ray, Tapan
name: Zhu, Bing
name: Wang, Lai
name: Priess, Petra
name: Tian, Xianbin
name: Hourcade-Potelleret, Florence
name: J. Einolf, Heidi
Publisher: name: Taylor & Francis
Year: 2019
Subjects: subject: Biochemistry
subject: Space Science
subject: Medicine
subject: Microbiology
subject: FOS: Biological sciences
subject: Cell Biology
subject: Molecular Biology
subject: Physiology
subject: Pharmacology
subject: Environmental Sciences not elsewhere classified
subject: Chemical Sciences not elsewhere classified
subject: Ecology
subject: Immunology
subject: FOS: Clinical medicine
subject: Marine Biology
subject: Cancer
subject: Inorganic Chemistry
subject: FOS: Chemical sciences
subject: Hematology
subject: Infectious Diseases
subject: FOS: Health sciences
subject: Virology
subject: Computational Biology

description: Asciminib is a potent, specific BCR-ABL1 inhibitor being developed for the treatment of patients with chronic myelogenous leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL).Here, we present the results of human oral absorption, distribution, metabolism, excretion (ADME) and <i>in vitro</i> studies that together provide an overall understanding of the metabolism, distribution and clearance of asciminib in humans.Asciminib was rapidly absorbed with a maximum plasma concentration at two hours post-dose. Total radioactivity and asciminib showed similar terminal half-lives in plasma.Oral asciminib absorption ranged between a minimum of 33%, and a maximum of 57% based on the metabolite profiles of late time-point feces collections.Asciminib was eliminated mainly through feces <i>via</i> unchanged asciminib excretion and metabolism.Direct glucuronidation and oxidation were major metabolic pathways in human that were catalyzed predominantly by UDP-glucuronosyltransferase (UGT)2B7 and cytochrome P450 (CYP)3A4, respectively.The relative contribution of the glucuronidation pathway to the total clearance of asciminib via metabolism is estimated to range ∼28–58%, whereas the relative contribution of the oxidative pathway is estimated to range ∼37–64%, based upon the maximum oral absorption in humans. Asciminib is a potent, specific BCR-ABL1 inhibitor being developed for the treatment of patients with chronic myelogenous leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL). Here, we present the results of human oral absorption, distribution, metabolism, excretion (ADME) and <i>in vitro</i> studies that together provide an overall understanding of the metabolism, distribution and clearance of asciminib in humans. Asciminib was rapidly absorbed with a maximum plasma concentration at two hours post-dose. Total radioactivity and asciminib showed similar terminal half-lives in plasma. Oral asciminib absorption ranged between a minimum of 33%, and a maximum of 57% based on the metabolite profiles of late time-point feces collections. Asciminib was eliminated mainly through feces <i>via</i> unchanged asciminib excretion and metabolism. Direct glucuronidation and oxidation were major metabolic pathways in human that were catalyzed predominantly by UDP-glucuronosyltransferase (UGT)2B7 and cytochrome P450 (CYP)3A4, respectively. The relative contribution of the glucuronidation pathway to the total clearance of asciminib via metabolism is estimated to range ∼28–58%, whereas the relative contribution of the oxidative pathway is estimated to range ∼37–64%, based upon the maximum oral absorption in humans.