title: Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody-drug conjugate in development for the treatment of HER2-positive cancer.
abstract: OBJECTIVE
  Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprising trastuzumab and DM1, a microtubule polymerization inhibitor, covalently bound via a stable thioether linker. To characterize the pharmacokinetics (PK) of T-DM1 in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, data from four studies (TDM3569g, TDM4258g, TDM4374g, and TDM4688g) of single-agent T-DM1 administered at 3.6 mg/kg every 3 weeks (q3w) were assessed in aggregate.
  
  
  METHODS
  Multiple analytes-T-DM1, total trastuzumab (TT), DM1, and key metabolites-were quantified using enzyme-linked immunosorbent assays or liquid chromatography tandem mass spectrometry. PK parameters of T-DM1, TT, and DM1 exposure were calculated using standard noncompartmental approaches and correlated to efficacy (objective response rate) and safety (platelet counts, hepatic transaminase concentrations). Immunogenicity was evaluated by measuring anti-therapeutic antibodies (ATA) to T-DM1 after repeated dosing using validated bridging antibody electrochemiluminescence or enzyme-linked immunosorbent assays.
  
  
  RESULTS
  PK parameters for T-DM1, TT, and DM1 were consistent across studies at cycle 1 and steady state. T-DM1 PK was not affected by residual trastuzumab from prior therapy or circulating extracellular domain of HER2. No significant correlations were observed between T-DM1 exposure and efficacy, thrombocytopenia, or increased concentrations of transaminases. Across the studies, ATA formation was detected in 4.5% (13/286) of evaluable patients receiving T-DM1 q3w.
  
  
  CONCLUSIONS
  The PK profile of single-agent T-DM1 (3.6 mg/kg q3w) is predictable, well characterized, and unaffected by circulating levels of HER2 extracellular domain or residual trastuzumab. T-DM1 exposure does not correlate with clinical responses or key adverse events.
authors.affiliation: Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA. girish.sandhya@gene.com
authors.forename: Sandhya
authors.initials: S
authors.lastname: Girish
authors.forename: Manish
authors.initials: M
authors.lastname: Gupta
authors.forename: Bei
authors.initials: B
authors.lastname: Wang
authors.forename: Dan
authors.initials: D
authors.lastname: Lu
authors.forename: Ian E
authors.initials: IE
authors.lastname: Krop
authors.forename: Charles L
authors.initials: CL
authors.lastname: Vogel
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris Iii
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.forename: Joo-Hee
authors.initials: JH
authors.lastname: Yi
authors.forename: Ola
authors.initials: O
authors.lastname: Saad
authors.forename: Barbara
authors.initials: B
authors.lastname: Tong
authors.forename: Yu-Waye
authors.initials: YW
authors.lastname: Chu
authors.forename: Scott
authors.initials: S
authors.lastname: Holden
authors.forename: Amita
authors.initials: A
authors.lastname: Joshi
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002853:Chromatography, Liquid; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008453:Maytansine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab