TY - JOUR T1 - Bioavailability, Biotransformation, and Excretion of the Covalent BTK Inhibitor Acalabrutinib in Rats, Dogs, and Humans JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.118.084459 SP - dmd.118.084459 AU - Terry Podoll AU - Paul G. Pearson AU - Jerry Evarts AU - Tim Ingallinera AU - Elena Bibikova AU - Hao Sun AU - Mark Gohdes AU - Kristen Cardinal AU - Mitesh Sanghvi AU - J. Greg Slatter Y1 - 2018/01/01 UR - http://dmd.aspetjournals.org/content/early/2018/11/13/dmd.118.084459.abstract N2 - Acalabrutinib is a targeted, covalent inhibitor of Bruton tyrosine kinase (BTK) with a unique 2-butynamide warhead that has relatively lower reactivity than other marketed acrylamide covalent inhibitors. A human [14C] microtracer bioavailability study in healthy subjects revealed moderate intravenous clearance (39.4 l/h) and an absolute bioavailability of 25.3 ± 14.3% (N = 8). Absorption and elimination of acalabrutinib following a 100 mg [14C] microtracer acalabrutinib oral dose were rapid, with maximum concentration reached in <1 h and elimination half-life values <2 h. Low concentrations of radioactivity persisted longer in the blood cell fraction and a peripheral blood mononuclear cell (PBMC) subfraction (enriched in target BTK) relative to plasma. [14C]acalabrutinib was extensively metabolized to over three dozen metabolites detectable by liquid chromatography-tandem mass spectrometry (LC-MS/MS), with primary metabolism by cytochrome P450 (CYP) 3A-mediated oxidation of the pyrrolidine ring, thiol conjugation of the butynamide warhead, and amide hydrolysis. A major active, circulating, pyrrolidine ring-opened metabolite, ACP-5862, was produced by CYP3A oxidation. Novel enol thioethers from the 2-butynamide warhead arose from glutathione and/or cysteine Michael additions and were subject to hydrolysis to a β-ketoamide. Total radioactivity recovery was 95.7 ± 4.6% (n = 6), with 12.0% of dose in urine and 83.5% in feces. Excretion and metabolism characteristics were generally similar in rat and dog. Acalabrutinib's highly selective, covalent mechanism of action, coupled with rapid absorption and elimination, enables high and sustained BTK target occupancy following twice daily administration. ER -