Abstract A136: Nonclinical disposition, metabolism, and in vitro drug-drug interaction assessment of DM1, a component of trastuzumab emtansine (T-DM1).
Authors: Wong Susan , Bumbaca Daniela , Yue Qin , Halladay Jason , Kenny Jane R. , Salphati Laurent , Saad Ola , Tibbitts Jay , Khojasteh Cyrus , Girish Sandhya , Shen Ben-Quan 
Published: June 2012

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. T-DM1 is composed of trastuzumab, a stable linker, and the microtubule polymerization inhibitor DM1, a derivative of maytansine. After binding to HER2 on tumor cells, T-DM1 undergoes receptor-mediated internalization and is expected to go through proteolytic degradation and catabolism, resulting in the directed delivery of DM1 to the tumor cells overexpressing HER2.

Although catabolism and elimination of T-DM1 have been reported previously, little is known about the metabolism and elimination of the DM1 component. This abstract summarizes aspects of the metabolism and distribution of DM1 to further the understanding of its disposition and potential for T-DM1 drug-drug interactions.

In vivo disposition and metabolism in rats: [3H]-DM1 at 91 μCi/kg (200 μg/kg) was administered to rats via a bolus intravenous injection. Blood, various tissues, urine, bile and feces were collected over the following 3 to 5 days and analyzed for radioactivity. DM1 distributed rapidly and extensively to the lungs, liver, kidneys, spleen, heart, gastrointestinal tract, and adrenal glands. The major route of excretion of DM1 was through the bile/feces, with a minimal amount excreted in the urine. A good mass balance (∼100% recovery of the injected dose) was achieved over 5 days. DM1 was extensively metabolized to multiple metabolites through oxidation, hydrolysis, methylation, and glutathione conjugations.

In vitro metabolism and potential for drug-drug interactions: To identify the major human cytochrome P450 (CYP) isoforms responsible for the metabolism of DM1 and determine the metabolites formed, DM1 was incubated in human liver microsomes (HLMs) in the presence of selective chemical inhibitors and with human recombinant CYP. The results of these studies demonstrated that DM1 was metabolized mainly by CYP3A4 and, to a lesser extent, by CYP3A5. The oxidative and hydrolysis metabolites of DM1 were detected in the in vitro incubation.

The induction and inhibitory properties of DM1 on CYP were evaluated using cryopreserved human hepatocytes and HLMs, respectively. DM1 was found to be neither an inducer nor an inhibitor of major CYP isoforms up to the highest concentrations tested at 1 μM (738 ng/mL) and 0.7 μM (500 ng/mL), respectively. In addition, a monolayer assay using MDCKII-MDR1 cells assessed the potential of DM1 as a substrate and inhibitor of the P-glycoprotein (P-gp) transporter. DM1 was found to be a substrate, but not an inhibitor, of P-gp when tested at 0.5 M (369 ng/mL).

Conclusion: Collectively, the in vitro data suggest that the DM1 component of T-DM1 has little potential for drug-drug interactions as a perpetrator, especially considering the low systemic exposure of DM1 (averaging 5 ng/mL or 0.007 μM) achieved in clinical studies and its lack of inhibition of CYP catalytic activities and P-gp activity at clinically relevant concentrations. This is consistent with the lack of evidence of drug-drug interaction observed in phase Ib/II clinical studies of T-DM1 combined with pertuzumab and taxanes.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A136.