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

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


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.

Publication types

  • Clinical Trial, Phase I
  • Comparative Study
  • Multicenter Study

MeSH terms

  • Administration, Intravenous
  • Ado-Trastuzumab Emtansine
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents, Immunological / administration & dosage
  • Antineoplastic Agents, Immunological / pharmacokinetics*
  • Breast Neoplasms / blood*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Cohort Studies
  • Female
  • Humans
  • Liver / drug effects*
  • Liver / metabolism
  • Liver Diseases / blood*
  • Liver Diseases / drug therapy
  • Liver Neoplasms / blood
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / secondary
  • Maytansine / administration & dosage
  • Maytansine / analogs & derivatives*
  • Maytansine / pharmacokinetics
  • Middle Aged
  • Receptor, ErbB-2* / genetics
  • Trastuzumab / administration & dosage
  • Trastuzumab / pharmacokinetics*


  • Antineoplastic Agents, Immunological
  • Maytansine
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Trastuzumab
  • Ado-Trastuzumab Emtansine