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Model-Based Evaluation and Optimization of Cardiac Monitoring Protocols for Adjuvant Treatment of Breast Cancer with Trastuzumab

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ABSTRACT

Purpose

Trastuzumab treatment is associated with occurrence of cardiac toxicity, for which monitoring of the left ventricular ejection fraction (LVEF) is indicated. The performance of the currently used monitoring protocol as defined in the summary of product characteristics (SPC) is however unknown. The objective of this analysis was to develop a model-based framework for evaluation and optimization of cardiac monitoring strategies.

Methods

The model-based framework comprised a previously developed exposure-response model for trastuzumab induced changes in LVEF, and a protocol-execution model that allowed incorporation of treatment interventions as described by a monitoring protocol. Metrics for evaluation of toxicity, dose intensity and monitoring burden were defined to allow evaluation and optimization of cardiac monitoring protocols.

Results

The success of a protocol-defined dose reduction was improved from 40% for the SPC-based protocol, to 79% for a scoring-based protocol, thereby decreasing the observed severity of cardiotoxicity. Including adaptation based on risk-profile allowed reduction of the mean number of LVEF measurements by 19%.

Conclusions

This model-based evaluation approach enabled evaluation and optimization of cardiac monitoring protocols that would be difficult to evaluate in a clinical setting. This approach can potentially be applied for other drugs that use repeated evaluation of continuous biomarkers for toxicity.

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Abbreviations

AUC45 :

area below a LVEF threshold of 45% and above the LVEF time curve

FT-AUC45 :

full-treatment AUC45

LVEF:

left ventricular ejection fraction

O-AUC45 :

observed AUC45

PD:

pharmacodynamics

PK:

pharmacokinetics

SPC:

summary of product characteristics

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ACKNOWLEDGMENTS and Disclosures

No funding was received for the conduct of this project. The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    J. G. Coen van Hasselt, Jan H. M. Schellens, Jos H. Beijnen & Alwin D. R. Huitema

  2. Department of Pharmacy and Pharmacology, Netherlands Cancer Institute/Slotervaart Hospital, Louwesweg 6, PO Box 90440, 1006 BK, Amsterdam, The Netherlands

    J. G. Coen van Hasselt, Jos H. Beijnen & Alwin D. R. Huitema

  3. Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

    Jan H. M. Schellens & Jos H. Beijnen

  4. Department of Cardiology, Slotervaart Hospital, Amsterdam, The Netherlands

    Melvin R. Mac Gillavry

Authors
  1. J. G. Coen van Hasselt
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  2. Jan H. M. Schellens
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  3. Melvin R. Mac Gillavry
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  4. Jos H. Beijnen
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  5. Alwin D. R. Huitema
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Correspondence to J. G. Coen van Hasselt.

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van Hasselt, J.G.C., Schellens, J.H.M., Mac Gillavry, M.R. et al. Model-Based Evaluation and Optimization of Cardiac Monitoring Protocols for Adjuvant Treatment of Breast Cancer with Trastuzumab. Pharm Res 29, 3499–3511 (2012). https://doi.org/10.1007/s11095-012-0845-y

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  • DOI: https://doi.org/10.1007/s11095-012-0845-y

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