A Phase I Pharmacokinetic Study of Trastuzumab Emtansine (T-DM1) in Patients with Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer and Normal or Reduced Hepatic Function
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The aim of this study was to evaluate the pharmacokinetics (PK) of trastuzumab emtansine (T-DM1) and relevant analytes in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer and hepatic impairment.
Patients were enrolled in three independent parallel cohorts based on hepatic function per Child–Pugh criteria: normal hepatic function, mild hepatic impairment, and moderate hepatic impairment. Patients received T-DM1 3.6 mg/kg intravenously every 3 weeks. PK samples were collected during cycles 1 and 3, and the PK of T-DM1 and relevant analytes were characterized and compared across cohorts.
Compared with patients with normal hepatic function (n = 10), T-DM1 clearance at cycle 1 was 1.8- and 4.0-fold faster in the mild (n = 10) and moderate (n = 8) cohorts, respectively. The trend of faster clearance was less apparent in cycle 3, with similar T-DM1 clearance across cohorts (mean ± standard deviation 8.16 ± 3.27 [n = 9], 9.74 ± 3.62 [n = 7], and 8.99 and 10.2 [individual values, n = 2] mL/day/kg for the normal, mild, and moderate cohorts, respectively). T-DM1 clearance at cycle 1 correlated significantly with baseline albumin, aspartate aminotransferase, and HER2 extracellular domain concentrations (p < 0.05). Plasma concentrations of DM1 and DM1-containing catabolites were low and were comparable across cohorts.
No increase in systemic DM1 concentration was observed in patients with mild or moderate hepatic impairment versus those with normal hepatic function. The faster T-DM1 clearance observed at cycle 1 in patients with hepatic impairment appeared to be transient. After repeated dosing (three cycles), T-DM1 exposure in patients with mild and moderate hepatic impairment was within the range seen in those with normal hepatic function.
KeywordsTrastuzumab Hepatic Impairment Brentuximab Vedotin Moderate Hepatic Impairment Normal Hepatic Function
The authors would like to thank the patients and all investigators for their participation in this trial. Patients with mild and moderate hepatic impairment were enrolled by Dr. Jean-Pierre Delort, Dr. Miguel Martin Jimenez, Dr. Joan Albanell Mestres, Dr. Lowell Hart, and Dr. Howard Burris. Please see Online Resource 1 for the full list of study investigators. The authors also thank Mr. Uwe Ziegler, F. Hoffmann-La Roche Ltd, for his support with the statistical analysis. Support for third-party medical writing assistance for this manuscript was provided by F. Hoffmann-La Roche Ltd.
Compliance with Ethical Standards
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
This work was supported by F. Hoffmann-La Roche Ltd.
Conflicts of interest
Chunze Li is an employee of Genentech, Inc. and owns stock in F. Hoffmann-La Roche Ltd and Genentech, Inc. Priya Agarwal, Nataliya Chernyukhin, and Sandhya Girish are employees of and own stock in Genentech, Inc. Ekaterina Gibiansky is a consultant to Genentech, Inc. Jin Yan Jin is an employee of Genentech, Inc. and owns stock in F. Hoffmann-La Roche Ltd and Eli Lilly. Susan Dent received honoraria from F. Hoffmann-La Roche Ltd and Amgen, Inc. Anthony Gonçalves received honoraria/consulting fees, support for travel, and non-financial support from F. Hoffmann-La Roche Ltd. Ihsan Nijem is an employee of Genentech, Inc. and owns stock in F. Hoffmann-La Roche Ltd. Alexander Strasak and Marie-Laurence Harle-Yge are employees of and own stock in F. Hoffmann-La Roche Ltd. Pat LoRusso received honoraria and non-financial support (e.g. provision of writing assistance, medicines, equipment, or administrative support) from, and has served as a consultant to, Genentech, Inc.
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