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An Integrated Multiple-Analyte Pharmacokinetic Model to Characterize Trastuzumab Emtansine (T-DM1) Clearance Pathways and to Evaluate Reduced Pharmacokinetic Sampling in Patients with HER2-Positive Metastatic Breast Cancer

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Abstract

Background and Objective

Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate recently approved by the US Food and Drug Administration for the treatment of human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer previously treated with trastuzumab and taxane chemotherapy. It comprises the microtubule inhibitory cytotoxic agent DM1 conjugated to the HER2-targeted humanized monoclonal antibody trastuzumab via a stable linker. To characterize the pharmacokinetics of T-DM1 in patients with metastatic breast cancer, concentrations of multiple analytes were quantified, including serum concentrations of T-DM1 conjugate and total trastuzumab (the sum of conjugated and unconjugated trastuzumab), as well as plasma concentrations of DM1. The clearance of T-DM1 conjugate is approximately 2 to 3 times faster than its parent antibody, trastuzumab. However, the clearance pathways accounting for this faster clearance rate are unclear. An integrated population pharmacokinetic model that simultaneously fits the pharmacokinetics of T-DM1 conjugate and total trastuzumab can help to elucidate the clearance pathways of T-DM1. The model can also be used to predict total trastuzumab pharmacokinetic profiles based on T-DM1 conjugate pharmacokinetic data and sparse total trastuzumab pharmacokinetic data, thereby reducing the frequency of pharmacokinetic sampling.

Methods

T-DM1 conjugate and total trastuzumab serum concentration data, including baseline trastuzumab concentrations prior to T-DM1 treatment, from phase I and II studies were used to develop this integrated population pharmacokinetic model. Based on a hypothetical T-DM1 catabolism scheme, two-compartment models for T-DM1 conjugate and trastuzumab were integrated by assuming a one-step deconjugation clearance from T-DM1 conjugate to trastuzumab. The ability of the model to predict the total trastuzumab pharmacokinetic profile based on T-DM1 conjugate pharmacokinetics and various sampling schemes of total trastuzumab pharmacokinetics was assessed to evaluate total trastuzumab sampling schemes.

Results

The final model reflects a simplified catabolism scheme of T-DM1, suggesting that T-DM1 clearance pathways include both deconjugation and proteolytic degradation. The model fits T-DM1 conjugate and total trastuzumab pharmacokinetic data simultaneously. The deconjugation clearance of T-DM1 was estimated to be ~0.4 L/day. Proteolytic degradation clearances for T-DM1 and trastuzumab were similar (~0.3 L/day). This model accurately predicts total trastuzumab pharmacokinetic profiles based on T-DM1 conjugate pharmacokinetic data and sparse total trastuzumab pharmacokinetic data sampled at preinfusion and end of infusion in cycle 1, and in one additional steady state cycle.

Conclusions

This semi-mechanistic integrated model links T-DM1 conjugate and total trastuzumab pharmacokinetic data, and supports the inclusion of both proteolytic degradation and deconjugation as clearance pathways in the hypothetical T-DM1 catabolism scheme. The model attributes a faster T-DM1 conjugate clearance versus that of trastuzumab to the presence of a deconjugation process and suggests a similar proteolytic clearance of T-DM1 and trastuzumab. Based on the model and T-DM1 conjugate pharmacokinetic data, a sparse pharmacokinetic sampling scheme for total trastuzumab provides an entire pharmacokinetic profile with similar predictive accuracy to that of a dense pharmacokinetic sampling scheme.

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Acknowledgments

The authors acknowledge the investigators, patients and their families who participated in these clinical trials. The authors acknowledge Jin Yan Jin, PhD, for scientific input and helpful discussions during the preparation of this report. Support for third-party editorial assistance for this manuscript, furnished by Denise Chun, Ph.D. (CodonMedical), was provided by Genentech, Inc. The clinical studies reported here were sponsored by Genentech, Inc. Dan Lu, Amita Joshi, Bei Wang, Steve Olsen, Joo-Hee Yi and Sandhya Girish are employees of Genentech, Inc., and have Roche stock/stock options. Ian E. Krop receives clinical trial support from Genentech, Inc. Howard A. Burris has no conflicts of interest to declare.

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Authors and Affiliations

  1. Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA

    Dan Lu, Amita Joshi, Bei Wang, Steve Olsen, Joo-Hee Yi & Sandhya Girish

  2. Dana-Farber Cancer Institute, Boston, MA, USA

    Ian E. Krop

  3. Sarah Cannon Research Institute, Nashville, TN, USA

    Howard A. Burris

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  1. Dan Lu
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Correspondence to Dan Lu.

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Lu, D., Joshi, A., Wang, B. et al. An Integrated Multiple-Analyte Pharmacokinetic Model to Characterize Trastuzumab Emtansine (T-DM1) Clearance Pathways and to Evaluate Reduced Pharmacokinetic Sampling in Patients with HER2-Positive Metastatic Breast Cancer. Clin Pharmacokinet 52, 657–672 (2013). https://doi.org/10.1007/s40262-013-0060-y

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