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.
Keywords: Absorption, antibody-drug conjugate, catabolism, distribution, excretion, metabolism, T-DM1, trastuzumab emtansine, Pharmacokinetic, Trastuzumab Emtansine, HER2, Plasma, breast cancer.
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