title: 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.
abstract: 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.
authors.affiliation: Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA. li.chunze@gene.com.
authors.forename: Chunze
authors.initials: C
authors.lastname: Li
authors.affiliation: Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Agarwal
authors.affiliation: QuantPharm LLC, North Potomac, MD, USA.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Gibiansky
authors.affiliation: Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA.
authors.forename: Jin Yan
authors.initials: JY
authors.lastname: Jin
authors.affiliation: The Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Susan
authors.initials: S
authors.lastname: Dent
authors.affiliation: Institut Paoli-Calmettes, Marseille, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Gonçalves
authors.affiliation: Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA.
authors.forename: Ihsan
authors.initials: I
authors.lastname: Nijem
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Strasak
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Marie-Laurence
authors.initials: ML
authors.lastname: Harle-Yge
authors.affiliation: Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Chernyukhin
authors.affiliation: Yale Cancer Center, Yale University, New Haven, CT, USA.
authors.forename: Pat
authors.initials: P
authors.lastname: LoRusso
authors.affiliation: Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Girish
mesh_terms: D061605:Administration, Intravenous; D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000074322:Antineoplastic Agents, Immunological / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008107:Liver Diseases / Q000097:blood* / Q000188:drug therapy; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy / Q000556:secondary; D008453:Maytansine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D000068878:Trastuzumab / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D000074322:Antineoplastic Agents, Immunological; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: Brentuximab Vedotin; Hepatic Impairment; Moderate Hepatic Impairment; Normal Hepatic Function; Trastuzumab