Population-estimated clearance of Trastuzumab Emtansine (T-DM1)
Estimates the clearance of Trastuzumab Emtansine (T-DM1), a HER2-targeted antibody-drug conjugate, in patients with HER2-positive metastatic breast cancer. The model was based on pooled data from a phase I trial and 2 phase II trials.
Research authors: Gupta M, Lorusso PM, Wang B, Yi JH, Burris HA 3rd, Beeram M, Modi S, Chu YW, Agresta S, Klencke B, Joshi A, Girish S.
Details Formula Study characteristics Files & References
★★★
Model author
Model ID
477
Version
1.15
Revision date
2021-02-17
MeSH terms
  • Pharmacokinetics
  • Breast Cancer
  • Neoplasm Metastasis
  • Model type
    Custom model (Calculation)
    Status
    public
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    Formula

    Additional information

    This study by Gupta et al1 (2012) included data from a phase I study2 and 2 phase II studies3,4. Patients enrolled in these studies had HER2-positive metastatic breast cancer.

    Assessment of model performance: 
    To assess the predictive performance of the final pharmacokinetic model, a visual predictive check (VPC) was performed.1 Replicates (n = 1000) of the original data set were simulated using the fixed and random effect parameters of the final model, and the observed PK data were plotted against the 90% prediction intervals of the simulated data. In addition, a nonparametric bootstrapping approach was used to evaluate the model stability and confidence intervals of the final parameter estimates. 

    References: 
    1Gupta M, Lorusso PM, Wang B et al. Clinical implications of pathophysiological and demographic covariates on the population pharmacokinetics oftrastuzumab emtansine, a HER2- targeted antibody-drug conjugate, in patients with HER2-positive metastaticbreast cancer. Journal of Clinical Pharmacology, 2012;52:691-703.
    2Krop IE, Beeram M, Modi S, et al. Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol. 2010;28:2698-2704.
    3Burris H, Rugo H, Vukelka S, et al. Phase II study of the antibody drug conjugate trastuzumab-DM1 (T-DM1) for the treatment of HER2-positive breast cancer following prior HER2-directed therapy. J Clin Oncol. 2011;29:398-405.
    4Krop IE, LoRusso PM, Miller KD, et al. A phase 2 study of the HER2 antibody-drug conjugate trastuzumab-DM1 (T-DM1) in patients (pts) with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab, lapatinib, and chemotherapy. Presented at: European Society for Medical Oncology Annual Symposium; October 8-12, 2010; Milan, Italy. (No digital link avialable).
     

    Study Population

    Total population size: 275
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    Females: {{ model.numberOfFemales }}

    Continuous characteristics

    Name Mean SD Unit
    Age 54 10 years
    Weight 72.1 17.7 kg
    Height 163 7 cm
    Body mass index 27.1 6.2 kg/m2
    Serum creatinine 75 56 umol/l
    Creatinine clearance 96 34 ml/min
    Albumin 39 5 g/l
    Total protein 70.4 7.3 g/l
    Total bilirubin 8.1 5.3 umol/l
    Aspartate aminotransferase 39 28 IU/l
    Alanine aminotransferase 31 21 IU/L
    Serum HER2 ECD expression 84.4 125.8 ng/ml
    Baseline trastuzumab 10.7 19.7 ug/ml
    Tumor burden 9.3 7.2 cm
    Population-estimated clearance of Trastuzumab Emtansine (T-DM1)
    V-1.15-477.21.02.17
    Refer to Intended Use for instructions before use
    Evidencio B.V., Irenesingel 19, 7481 GJ, Haaksbergen, the Netherlands

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    Result
    Note
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    Population-estimated clearance of trastuzumab emtansine L/d

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    Outcome stratification

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    Conditional information

    Result interpretation

    This population pharmacokinetic (PK) model by Gupta et al1 estimates the clearance of trastuzumab emtansine (T-DM1) based on a large and representative patient population that has received prior trastuzumab-based therapy. This model should support exposure comparisons of different dosage regimens, as well as PK and pharmacodynamic studies of T-DM1. Patients with larger body weight, lower albumin, higher tumor burden, and higher AST had faster clearance. Creatinine clearance was found to have no influence on T-DM1 clearance.1

    Limitations of the model:
    The applicability of the derived population PK model might be limited to the T-DM1 concentration ranges where PK is linear. The PK of T-DM1 in patients on earlier lines of therapy has yet to be fully elucidated from ongoing trials.1

    Model performance: 
    In a study by Gupta et al (2012), there was good agreement between observed and predicted concentrations. The goodness-of-fit plots for the model demonstrated good agreement between the observed and predicted concentration values.
    Body weight, albumin, tumor burden, and AST were statistically significant covariates that influenced the pharmacokinetics of T-DM1, explaining 37%
    of interindividual variance in the clearance of T-DM1. Interindividual variability of clearance was reduced from 26.4% to 21% (decrease of 36.7%) after adding the models' covariates.1 


    References: 
    1Gupta M, Lorusso PM, Wang B et al. Clinical implications of pathophysiological and demographic covariates on the population pharmacokinetics oftrastuzumab emtansine, a HER2- targeted antibody-drug conjugate, in patients with HER2-positive metastaticbreast cancer. Journal of Clinical Pharmacology, 2012;52:691-703.
     

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    Calculations alone should never dictate patient care, and are no substitute for professional judgement. See our full disclaimer.

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