title: A population pharmacokinetic/pharmacodynamic model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancer.
abstract: OBJECTIVE
  Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in the development for the treatment of human epidermal growth factor receptor 2-positive cancers. Thrombocytopenia (TCP) is the dose-limiting toxicity of T-DM1. A semimechanistic population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to characterize the effect of T-DM1 on patient platelet counts.
  
  
  METHODS
  A PK/PD model with transit compartments that mimic platelet development and circulation was fit to concentration-platelet-time course data from two T-DM1 single-agent studies (TDM3569g; N = 52 and TDM4258g; N = 112). NONMEM(®) 7 software was used for model development. Data from a separate phase II study (TDM4374g; N = 110) were used for model evaluation. Patient baseline characteristics were evaluated as covariates of model PD parameters.
  
  
  RESULTS
  The model described the platelet data well and predicted the incidence of grade ≥3 TCP. The model predicted that with T-DM1 3.6 mg/kg given every 3 weeks (q3w), the lowest platelet nadir would occur after the first dose. Also predicted was a patient subgroup (46 %) having variable degrees of downward drifting platelet-time profiles, which were predicted to stabilize by the eighth treatment cycle to platelet counts above grade 3 TCP. Baseline characteristics were not significant covariates of PD parameters in the model.
  
  
  CONCLUSIONS
  This semimechanistic PK/PD model accurately captures the cycle 1 platelet nadir, the downward drift noted in some patient platelet-time profiles, and the ~8 % incidence of grade ≥3 TCP with T-DM1 3.6 mg/kg q3w. This model supports T-DM1 3.6 mg/kg q3w as a well-tolerated dose with minimal dose delays or reductions for TCP.
authors.affiliation: Genentech, Inc., South San Francisco, CA, USA. brendan.bender@farmbio.uu.se
authors.forename: Brendan C
authors.initials: BC
authors.lastname: Bender
authors.forename: Franziska
authors.initials: F
authors.lastname: Schaedeli-Stark
authors.forename: Reinhold
authors.initials: R
authors.lastname: Koch
authors.forename: Amita
authors.initials: A
authors.lastname: Joshi
authors.forename: Yu-Waye
authors.initials: YW
authors.lastname: Chu
authors.forename: Hope
authors.initials: H
authors.lastname: Rugo
authors.forename: Ian E
authors.initials: IE
authors.lastname: Krop
authors.forename: Sandhya
authors.initials: S
authors.lastname: Girish
authors.forename: Lena E
authors.initials: LE
authors.lastname: Friberg
authors.forename: Manish
authors.initials: M
authors.lastname: Gupta
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy*; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000009:adverse effects*; D008453:Maytansine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D008954:Models, Biological; D010976:Platelet Count; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D013921:Thrombocytopenia / Q000139:chemically induced*; D000068878:Trastuzumab
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D000922:Immunotoxins; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human