title: Catabolic fate and pharmacokinetic characterization of trastuzumab emtansine (T-DM1): an emphasis on preclinical and clinical catabolism.
abstract: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in clinical development for the treatment of human epidermal growth factor receptor 2 (HER2)-positive cancers. Herein, we describe a series of studies to assess T-DM1 absorption, distribution, metabolism, and excretion (ADME) in rats as well as to assess human exposure to T-DM1 catabolites. Following administration of unlabeled and radiolabeled T-DM1 in female Sprague Dawley rats as a single dose, plasma, urine, bile and feces were assessed for mass balance, profiling and identification of catabolites. In rats, the major circulating species in plasma was T-DM1, while DM1 concentrations were low (1.08 to 15.6 ng/mL). The major catabolites found circulating in rat plasma were DM1, [N-maleimidomethyl] cyclohexane-1- carboxylate-DM1 (MCC-DM1), and Lysine-MCC-DM1. These catabolites identified in rats were also detected in plasma samples from patients with HER2-positive metastatic breast cancer who received single-agent T-DM1 (3.6 mg/kg every 3 weeks) in a phase 2 clinical study. There was no evidence of tissue accumulation in rats or catabolite accumulation in human plasma following multiple dosing. In rats, T-DM1 was distributed nonspecifically to the organs without accumulation. The major pathway of DM1-containing catabolite elimination in rats was the fecal/biliary route, with up to 80% of radioactivity recovered in the feces and 50% in the bile. The rat T-DM1 ADME profile is likely similar to the human profile, although there may be differences since trastuzumab does not bind the rat HER2- like receptor. Further research is necessary to more fully understand the T-DM1 ADME profile in humans.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics, Genentech Inc., South San Francisco, CA 94080, USA. shen.ben@gene.com
authors.forename: Ben-Quan
authors.initials: BQ
authors.lastname: Shen
authors.forename: Daniela
authors.initials: D
authors.lastname: Bumbaca
authors.forename: Ola
authors.initials: O
authors.lastname: Saad
authors.forename: Qin
authors.initials: Q
authors.lastname: Yue
authors.forename: Cinthia V
authors.initials: CV
authors.lastname: Pastuskovas
authors.forename: S Cyrus
authors.initials: SC
authors.lastname: Khojasteh
authors.forename: Jay
authors.initials: J
authors.lastname: Tibbitts
authors.forename: Surinder
authors.initials: S
authors.lastname: Kaur
authors.forename: Bei
authors.initials: B
authors.lastname: Wang
authors.forename: Yu-Waye
authors.initials: YW
authors.lastname: Chu
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.forename: Sandhya
authors.initials: S
authors.lastname: Girish
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D008453:Maytansine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D008660:Metabolism / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D008453:Maytansine; D000068878:Trastuzumab; D000080044:Ado-Trastuzumab Emtansine