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Clin Pharmacokinet. 2017 Sep;56(9):1069-1080. doi: 10.1007/s40262-016-0496-y.

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.

Author information

1
Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA. li.chunze@gene.com.
2
Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA.
3
QuantPharm LLC, North Potomac, MD, USA.
4
The Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, ON, Canada.
5
Institut Paoli-Calmettes, Marseille, France.
6
F. Hoffmann-La Roche Ltd, Basel, Switzerland.
7
Yale Cancer Center, Yale University, New Haven, CT, USA.

Abstract

OBJECTIVE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

Brentuximab Vedotin; Hepatic Impairment; Moderate Hepatic Impairment; Normal Hepatic Function; Trastuzumab

PMID:
27995530
DOI:
10.1007/s40262-016-0496-y
[Indexed for MEDLINE]

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