title: Metabolic Disposition of Osimertinib in Rats, Dogs, and Humans: Insights into a Drug Designed to Bind Covalently to a Cysteine Residue of Epidermal Growth Factor Receptor.
abstract: Preclinical and clinical studies were conducted to determine the metabolism and pharmacokinetics of osimertinib and key metabolites AZ5104 and AZ7550. Osimertinib was designed to covalently bind to epidermal growth factor receptors, allowing it to achieve nanomolar cellular potency (Finlay et al., 2014). Covalent binding was observed in incubations of radiolabeled osimertinib with human and rat hepatocytes, human and rat plasma, and human serum albumin. Osimertinib, AZ5104, and AZ7550 were predominantly metabolized by CYP3A. Seven metabolites were detected in human hepatocytes, also observed in rat or dog hepatocytes at similar or higher levels. After oral administration of radiolabeled osimertinib to rats, drug-related material was widely distributed, with the highest radioactivity concentrations measured at 6 hours postdose in most tissues; radioactivity was detectable in 42% of tissues 60 days postdose. Concentrations of [(14)C]-radioactivity in blood were lower than in most tissues. After the administration of a single oral dose of 20 mg of radiolabeled osimertinib to healthy male volunteers, ∼19% of the dose was recovered by 3 days postdose. At 84 days postdose, mean total radioactivity recovery was 14.2% and 67.8% of the dose in urine and feces. The most abundant metabolite identified in feces was AZ5104 (∼6% of dose). Osimertinib accounted for ∼1% of total radioactivity in the plasma of non-small cell lung cancer patients after 22 days of 80-mg osimertinib once-daily treatment; the most abundant circulatory metabolites were AZ7550 and AZ5104 (<10% of total osimertinib-related material). Osimertinib is extensively distributed and metabolized in humans and is eliminated primarily via the fecal route.
authors.affiliation: AstraZeneca, Macclesfield (M.V.C., P.F., S.M., K.P., P.B.), Seda Pharmaceutical Development Services, Cheshire (P.A.D), and Quotient Clinical Ltd., Ruddington, United Kingdom (J.C.).
authors.forename: Paul A
authors.initials: PA
authors.lastname: Dickinson
authors.affiliation: AstraZeneca, Macclesfield (M.V.C., P.F., S.M., K.P., P.B.), Seda Pharmaceutical Development Services, Cheshire (P.A.D), and Quotient Clinical Ltd., Ruddington, United Kingdom (J.C.).
authors.forename: Mireille V
authors.initials: MV
authors.lastname: Cantarini
authors.affiliation: AstraZeneca, Macclesfield (M.V.C., P.F., S.M., K.P., P.B.), Seda Pharmaceutical Development Services, Cheshire (P.A.D), and Quotient Clinical Ltd., Ruddington, United Kingdom (J.C.).
authors.forename: Jo
authors.initials: J
authors.lastname: Collier
authors.affiliation: AstraZeneca, Macclesfield (M.V.C., P.F., S.M., K.P., P.B.), Seda Pharmaceutical Development Services, Cheshire (P.A.D), and Quotient Clinical Ltd., Ruddington, United Kingdom (J.C.).
authors.forename: Paul
authors.initials: P
authors.lastname: Frewer
authors.affiliation: AstraZeneca, Macclesfield (M.V.C., P.F., S.M., K.P., P.B.), Seda Pharmaceutical Development Services, Cheshire (P.A.D), and Quotient Clinical Ltd., Ruddington, United Kingdom (J.C.).
authors.forename: Scott
authors.initials: S
authors.lastname: Martin
authors.affiliation: AstraZeneca, Macclesfield (M.V.C., P.F., S.M., K.P., P.B.), Seda Pharmaceutical Development Services, Cheshire (P.A.D), and Quotient Clinical Ltd., Ruddington, United Kingdom (J.C.).
authors.forename: Kathryn
authors.initials: K
authors.lastname: Pickup
authors.affiliation: AstraZeneca, Macclesfield (M.V.C., P.F., S.M., K.P., P.B.), Seda Pharmaceutical Development Services, Cheshire (P.A.D), and Quotient Clinical Ltd., Ruddington, United Kingdom (J.C.) Peter.Ballard@astrazeneca.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Ballard
mesh_terms: D000178:Acrylamides; D000328:Adult; D000368:Aged; D000814:Aniline Compounds; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001665:Binding Sites; D001711:Biotransformation; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy*; D003545:Cysteine; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004285:Dogs; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D005260:Female; D022781:Hepatocytes / Q000201:enzymology; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D017208:Rats, Wistar; D000075462:Serum Albumin, Human / Q000378:metabolism; D014018:Tissue Distribution; D007211:Indoles; D011743:Pyrimidines
chemical_list: D000178:Acrylamides; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D003545:Cysteine; D051544:Cytochrome P-450 CYP3A; D066246:ErbB Receptors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D000075462:Serum Albumin, Human; C422455:ALB protein, human; C000596361:osimertinib; D007211:Indoles; D011743:Pyrimidines; C512478:EGFR protein, human; C483803:Egfr protein, rat