Bioavailability, Biotransformation, and Excretion of the Covalent Bruton Tyrosine Kinase Inhibitor Acalabrutinib in Rats, Dogs, and Humans

• Published in: Drug metabolism and disposition Vol. 47; no. 2; pp. 145 - 154
• Main Authors: Podoll, Terry, Pearson, Paul G., Evarts, Jerry, Ingallinera, Tim, Bibikova, Elena, Sun, Hao, Gohdes, Mark, Cardinal, Kristen, Sanghvi, Mitesh, Slatter, J. Greg
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2019; American Society for Pharmacology and Experimental Therapeutics, Inc
• Subjects: Absorption; Acrylamide; Administration, Oral; Adult; Agammaglobulinaemia Tyrosine Kinase - antagonists & inhibitors; Animals; Antineoplastic Agents - analysis; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Benzamide; Benzamides - analysis; Benzamides - metabolism; Benzamides - pharmacology; Bioavailability; Biological Availability; Biotransformation; Blood cells; Bruton's tyrosine kinase; Carbon 14; Conjugation; Covalence; Cytochrome P-450 CYP3A - metabolism; Dogs; Economic conditions; Enzyme inhibitors; Excretion; Feces - chemistry; Female; Glutathione; Half-Life; Healthy Volunteers; Humans; Hydrolysis; Inhibitors; Intestinal Absorption; Intravenous administration; Kinases; Liquid chromatography; Low concentrations; Lymphoma, Mantle-Cell - drug therapy; Male; Mass spectrometry; Mass spectroscopy; Metabolism; Metabolites; Middle Aged; Occupancy; Oxidation; Oxidation-Reduction; Peripheral blood; Protein Kinase Inhibitors - analysis; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacology; Pyrazines - analysis; Pyrazines - metabolism; Pyrazines - pharmacology; Pyrrolidine; Radioactive half-life; Radioactivity; Rats; Rats, Sprague-Dawley; Thioethers; Tyrosine; Tyrosine kinase inhibitors; Urine; Urine - chemistry; Young Adult; FDA; MS/MS; AUC; t1/2; ACP-5862; ACP-5461; GSH; LSC; HPLC; BCRP; ADME; MS; AMS; CL; GST; PBMC; CV; HER; LC; Tmax; ACP-5530; ACP-5134; BTK; ACP-5531; PK; TCI; ACP-5197

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 intravenou...