Clinical Pharmacokinetics

, Volume 56, Issue 9, pp 1069–1080 | Cite as

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

  • Chunze Li
  • Priya Agarwal
  • Ekaterina Gibiansky
  • Jin Yan Jin
  • Susan Dent
  • Anthony Gonçalves
  • Ihsan Nijem
  • Alexander Strasak
  • Marie-Laurence Harle-Yge
  • Nataliya Chernyukhin
  • Pat LoRusso
  • Sandhya Girish
Original Research Article

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.

Supplementary material

40262_2016_496_MOESM1_ESM.doc (2.7 mb)
Supplementary material 1 (DOC 2718 kb)

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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Chunze Li
    • 1
  • Priya Agarwal
    • 1
  • Ekaterina Gibiansky
    • 2
  • Jin Yan Jin
    • 1
  • Susan Dent
    • 3
  • Anthony Gonçalves
    • 4
  • Ihsan Nijem
    • 1
  • Alexander Strasak
    • 5
  • Marie-Laurence Harle-Yge
    • 5
  • Nataliya Chernyukhin
    • 1
  • Pat LoRusso
    • 6
  • Sandhya Girish
    • 1
  1. 1.Genentech, IncSouth San FranciscoUSA
  2. 2.QuantPharm LLCNorth PotomacUSA
  3. 3.The Ottawa Hospital Cancer CentreUniversity of OttawaOttawaCanada
  4. 4.Institut Paoli-CalmettesMarseilleFrance
  5. 5.F. Hoffmann-La Roche LtdBaselSwitzerland
  6. 6.Yale Cancer CenterYale UniversityNew HavenUSA

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