Cancer Chemotherapy and Pharmacology

, Volume 70, Issue 4, pp 591–601

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

  • Brendan C. Bender
  • Franziska Schaedeli-Stark
  • Reinhold Koch
  • Amita Joshi
  • Yu-Waye Chu
  • Hope Rugo
  • Ian E. Krop
  • Sandhya Girish
  • Lena E. Friberg
  • Manish Gupta
Original Article

DOI: 10.1007/s00280-012-1934-7

Cite this article as:
Bender, B.C., Schaedeli-Stark, F., Koch, R. et al. Cancer Chemother Pharmacol (2012) 70: 591. doi:10.1007/s00280-012-1934-7

Abstract

Purpose

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.

Keywords

Trastuzumab emtansineT-DM1ThrombocytopeniaPopulation pharmacokinetic/pharmacodynamic modelSemimechanisticCumulative TCP

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Brendan C. Bender
    • 1
    • 2
  • Franziska Schaedeli-Stark
    • 3
  • Reinhold Koch
    • 3
  • Amita Joshi
    • 1
  • Yu-Waye Chu
    • 1
  • Hope Rugo
    • 4
  • Ian E. Krop
    • 5
  • Sandhya Girish
    • 1
  • Lena E. Friberg
    • 2
  • Manish Gupta
    • 1
    • 6
  1. 1.Genentech, Inc.South San FranciscoUSA
  2. 2.Department of Pharmaceutical BiosciencesUppsala UniversityUppsalaSweden
  3. 3.F. Hoffman-La Roche Ltd.BaselSwitzerland
  4. 4.UCSF Helen Diller Family Comprehensive Cancer CenterSan FranciscoUSA
  5. 5.Dana–Farber Cancer InstituteBostonUSA
  6. 6.Bristol–Myers SquibbLawrencevilleUSA