title: Population pharmacokinetics of trastuzumab emtansine (T-DM1), a HER2-targeted antibody-drug conjugate, in patients with HER2-positive metastatic breast cancer: clinical implications of the effect of covariates.
abstract: OBJECTIVE
  Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprising the humanized monoclonal antibody trastuzumab linked to DM1, a highly potent cytotoxic agent. A population pharmacokinetic (PK) analysis was performed to estimate typical values and interindividual variability of T-DM1 PK parameters and the effects of clinically relevant covariates.
  
  
  METHODS
  Serum samples were collected from 671 patients with human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer (MBC) who received single-agent T-DM1 in five phase I to phase III studies. Nonlinear mixed-effects modeling with the first-order conditional estimation method was used.
  
  
  RESULTS
  A linear two-compartment model with first-order elimination from the central compartment described T-DM1 PKs in the clinical dose range. T-DM1 elimination clearance was 0.676 L/day, volume of distribution in the central compartment (V c) was 3.127 L, and terminal elimination half-life was 3.94 days. Age, race, region, and renal function did not influence T-DM1 PK. Given the low-to-moderate effect of all statistically significant covariates on T-DM1 exposure, none of these covariates is expected to result in a clinically meaningful change in T-DM1 exposure.
  
  
  CONCLUSIONS
  T-DM1 PK properties are consistent and predictable in patients. A further refinement of dose based on baseline covariates other than body weight for the current 3.6 mg/kg regimen would not yield clinically meaningful reductions in interindividual PK variability in patients with MBC.
authors.affiliation: Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA, lu.dan@gene.com.
authors.forename: Dan
authors.initials: D
authors.lastname: Lu
authors.forename: Sandhya
authors.initials: S
authors.lastname: Girish
authors.forename: Yuying
authors.initials: Y
authors.lastname: Gao
authors.forename: Bei
authors.initials: B
authors.lastname: Wang
authors.forename: Joo-Hee
authors.initials: JH
authors.lastname: Yi
authors.forename: Ellie
authors.initials: E
authors.lastname: Guardino
authors.forename: Meghna
authors.initials: M
authors.lastname: Samant
authors.forename: Melody
authors.initials: M
authors.lastname: Cobleigh
authors.forename: Mothaffar
authors.initials: M
authors.lastname: Rimawi
authors.forename: Pierfranco
authors.initials: P
authors.lastname: Conte
authors.forename: Jin Yan
authors.initials: JY
authors.lastname: Jin
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized / Q000097:blood / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000453:epidemiology / Q000378:metabolism* / Q000556:secondary; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D016014:Linear Models; D008453:Maytansine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014018:Tissue Distribution; D000068878:Trastuzumab; D014481:United States / Q000453:epidemiology
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human