Original Article

Cancer Chemotherapy and Pharmacology

, Volume 70, Issue 4, pp 591-601

First online:

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. BenderAffiliated withGenentech, Inc.Department of Pharmaceutical Biosciences, Uppsala University
  • , Franziska Schaedeli-StarkAffiliated withF. Hoffman-La Roche Ltd.
  • , Reinhold KochAffiliated withF. Hoffman-La Roche Ltd.
  • , Amita JoshiAffiliated withGenentech, Inc.
  • , Yu-Waye ChuAffiliated withGenentech, Inc.
  • , Hope RugoAffiliated withUCSF Helen Diller Family Comprehensive Cancer Center
  • , Ian E. KropAffiliated withDana–Farber Cancer Institute
  • , Sandhya GirishAffiliated withGenentech, Inc. Email author 
  • , Lena E. FribergAffiliated withDepartment of Pharmaceutical Biosciences, Uppsala University
    • , Manish GuptaAffiliated withGenentech, Inc.Bristol–Myers Squibb

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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 emtansine T-DM1 Thrombocytopenia Population pharmacokinetic/pharmacodynamic model Semimechanistic Cumulative TCP