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Non-Clinical Disposition and Metabolism of DM1, a Component of Trastuzumab Emtansine (T-DM1), in Sprague Dawley Rats

[ Vol. 9 , Issue. 2 ]


Ben-Quan Shen, Daniela Bumbaca, Qin Yue, Ola Saad, Jay Tibbitts, S. Cyrus Khojasteh and Sandhya Girish   Pages 119 - 131 ( 13 )


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 [3H]-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.


Ado-trastuzumab emtansine, antibody–drug conjugate, disposition, DM1, metabolism, T-DM1, trastuzumab emtansine, percentage of injected dose.


Department of Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080 USA., Department of Clinical Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080 USA.

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