Tran Phi, Hanna Imad, Eggimann Fabian Kurt, Schoepfer Joseph, Ray Tapan, Zhu Bing, Wang Lai, Priess Petra, Tian Xianbin, Hourcade-Potelleret Florence, Einolf Heidi J
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Novartis Pharma AG, Basel, Switzerland.
Xenobiotica. 2020 Feb;50(2):150-169. doi: 10.1080/00498254.2019.1594449. Epub 2019 May 6.
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 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 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.
阿西替尼是一种强效、特异性的BCR-ABL1抑制剂，正在开发用于治疗慢性粒细胞白血病（CML）和费城染色体阳性急性淋巴细胞白血病（Ph+ALL）患者。在此，我们展示了人体口服吸收、分布、代谢、排泄（ADME）研究的结果，这些研究共同提供了对阿西替尼在人体内的代谢、分布和清除的全面理解。阿西替尼吸收迅速，给药后两小时达到最大血浆浓度。总放射性和阿西替尼在血浆中显示出相似的终末半衰期。根据晚期粪便收集的代谢物谱，口服阿西替尼的吸收范围在最低33%至最高57%之间。阿西替尼主要通过粪便消除，包括未改变的阿西替尼排泄和代谢。直接葡萄糖醛酸化和氧化是人体中的主要代谢途径，分别主要由尿苷二磷酸葡萄糖醛酸基转移酶（UGT）2B7和细胞色素P450（CYP）3A4催化。根据人体最大口服吸收情况，葡萄糖醛酸化途径对阿西替尼通过代谢的总清除率的相对贡献估计在约28-58%之间，而氧化途径的相对贡献估计在约37-64%之间。
