Catabolic fate and pharmacokinetic characterization of trastuzumab emtansine (T-DM1): An Emphasis on preclinical and clinical catabolism

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. © 2012 bentham science publishers.