Model-based evaluation and optimization of cardiac monitoring protocols for adjuvant treatment of breast cancer with trastuzumab.
OBJECTIVE
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.
Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. jgc.vanhasselt@gmail.com
J G Coen
JG
van Hasselt
Jan H M
JH
Schellens
Melvin R
MR
Mac Gillavry
Jos H
JH
Beijnen
Alwin D R
AD
Huitema
D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy*; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects*; D006801:Humans; D008954:Models, Biological; D000068878:Trastuzumab
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068878:Trastuzumab