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DDMODEL00000119: Bender_2012_thrombocytopenia_TDM1

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Short description:
Population PKPD model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancer
PharmML (0.6.1)
  • 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.
  • Bender BC, Schaedeli-Stark F, Koch R, Joshi A, Chu YW, Rugo H, Krop IE, Girish S, Friberg LE, Gupta M
  • Cancer chemotherapy and pharmacology, 10/2012, Volume 70, Issue 4, pages: 591-601
  • Genentech, Inc., South San Francisco, CA, USA. brendan.bender@farmbio.uu.se
  • 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.
Paolo Magni
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  • Model owner: Paolo Magni
  • Submitted: Dec 12, 2015 1:19:57 PM
  • Last Modified: Oct 13, 2016 6:06:21 PM
Revisions
  • Version: 7 public model Download this version
    • Submitted on: Oct 13, 2016 6:06:21 PM
    • Submitted by: Paolo Magni
    • With comment: Edited model metadata online.
  • Version: 5 public model Download this version
    • Submitted on: Jul 16, 2016 5:46:32 PM
    • Submitted by: Paolo Magni
    • With comment: Updated model annotations.
  • Version: 2 public model Download this version
    • Submitted on: Dec 12, 2015 1:19:57 PM
    • Submitted by: Paolo Magni
    • With comment: Edited model metadata online.
 
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