Non-Clinical Disposition and Metabolism of DM1, a Component of Trastuzumab Emtansine (T-DM1), in Sprague Dawley Rats.
2015
DM1, a derivative of maytansine, is the cytotoxic component of the antibody–drug
conjugate trastuzumab emtansine (T-DM1). Understanding the disposition and metabolism of DM1
would help to assess (1) any tissue-specific distribution and risk for potential drug–drug interactions
and (2) the need for special patient population studies. To this end, the current study determined the
disposition and metabolism of DM1 following single intravenous administration of [ 3 H]-DM1 in
Sprague Dawley rats. Blood, tissues, urine, bile, and feces were collected up to 5 days after dose
administration and analyzed for total radioactivity and metabolites. Results showed that radioactivity cleared rapidly from
the blood and quickly distributed to the lungs, liver, kidneys, spleen, heart, gastrointestinal tract, adrenal glands, and other
tissues without significant accumulation or persistence. The majority of dosed radioactivity was recovered in feces
(~100% of the injected dose over 5 days) with biliary elimination being the predominant route (~46% of the injected dose
over 3 days). Excretion in urine was minimal (~5% of the injected dose over 5 days). Mass balance was achieved over 5
days. An analysis of bile samples revealed a small fraction of intact DM1 and a predominance of DM1 metabolites
formed through oxidation, hydrolysis, S-methylation, and glutathione and its related conjugates. Collectively, these data
demonstrate that DM1 is extensively distributed and quickly cleared from blood, and undergoes extensive metabolism to
form multiple metabolites, which are mainly eliminated through the hepatic-biliary route, suggesting that hepatic function
(but not renal function) plays an important role in DM1 elimination.
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