Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Pharm Res. 2012 Dec;29(12):3499-511. doi: 10.1007/s11095-012-0845-y. Epub 2012 Aug 21.
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.
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.
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%.
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.
曲妥珠单抗治疗与心脏毒性的发生有关，因此需要监测左心室射血分数（LVEF）。然而，目前使用的监测方案在产品特性摘要（SPC）中的性能尚不清楚。本分析的目的是开发一种基于模型的框架，用于评估和优化心脏监测策略。
基于模型的框架包括先前开发的用于曲妥珠单抗诱导的 LVEF 变化的暴露-反应模型，以及允许根据监测方案中描述的治疗干预措施纳入的方案执行模型。定义了用于评估毒性、剂量强度和监测负担的指标，以允许评估和优化心脏监测方案。
与基于 SPC 的方案相比，方案定义的剂量减少的成功率从 40%提高到 79%，从而降低了观察到的心脏毒性的严重程度。包括基于风险状况的适应性允许减少平均 LVEF 测量次数 19%。
这种基于模型的评估方法能够评估和优化心脏监测方案，而这些方案在临床环境中很难评估。这种方法可能适用于其他使用连续生物标志物重复评估毒性的药物。
