Deppenweiler Marine, Falkowski Sabrina, Saint-Marcoux Franck, Monchaud Caroline, Picard Nicolas, Laroche Marie-Laure, Tubiana-Mathieu Nicole, Venat-Bouvet Laurence, Marquet Pierre, Woillard Jean-Baptiste
Department of Pharmacology, Toxicology and Pharmacovigilance, University Hospital of Limoges, France.
Department of Oncology, University Hospital of Limoges, France.
Pharmacol Res. 2017 Jul;121:138-144. doi: 10.1016/j.phrs.2017.04.029. Epub 2017 May 1.
Therapeutic drug monitoring (TDM) of everolimus is not performed in oncology and no trough level (C) target has been yet defined. The aim of this study was to determine everolimus C target for toxicity and efficacy.
Clinical, biological and radiologic data from 54 patients were collected. Toxicity event was defined by termination, temporary interruption and/or dose reduction of everolimus while efficacy was defined as progression-free survival. C values were dichotomized by ROC curve analysis and the association between exposure and outcome was determined using Cox models for repeated events (toxicity) or Cox model censured at the first event (progression free survival).
Among the 42 patients (77.8%) with breast cancer, 10 (18.5%) kidney cancer and 2 (3.7%) neuroendocrine cancer, adverse events were reported in 75.9% of the patients (everolimus termination in 25.9% patients). C everolimus higher than 26.3ng/mL (Sen=0.38,Spe=0.88) were associated with a 4-fold increased risk of toxicity (HR=4.12, IC95%=[1.48-11.5], p=0.0067) whereas C lower than 11.9ng/mL were associated with a 3-fold increased risk of progression (HR=3.2, IC95%=[1.33-7.81],p=0.001).
Further studies are required to evaluate the everolimus C threshold proposed for toxicity (26.3ng/mL) and for progression (11.9ng/mL) especially with a large number of patients and more homogeneous types of cancer. However, these results are in favour of TDM for everolimus in oncology.
依维莫司的治疗药物监测（TDM）在肿瘤学中尚未开展，且尚未确定谷浓度（C）目标值。本研究的目的是确定依维莫司毒性和疗效的C目标值。
收集了54例患者的临床、生物学和放射学数据。毒性事件定义为依维莫司的终止、暂时中断和/或剂量减少，而疗效定义为无进展生存期。通过ROC曲线分析将C值进行二分法分析，并使用重复事件的Cox模型（毒性）或首次事件时截尾的Cox模型（无进展生存期）确定暴露与结局之间的关联。
在42例（77.8%）乳腺癌、10例（18.5%）肾癌和2例（3.7%）神经内分泌癌患者中，75.9%的患者报告了不良事件（25.9%的患者终止使用依维莫司）。依维莫司C值高于26.3ng/mL（灵敏度=0.38，特异度=0.88）与毒性风险增加4倍相关（风险比=4.12，95%置信区间=[1.48-11.5]，p=0.0067），而C值低于11.9ng/mL与进展风险增加3倍相关（风险比=3.2，95%置信区间=[1.33-7.81]，p=0.001）。
需要进一步研究来评估所提出的依维莫司毒性（26.3ng/mL）和进展（11.9ng/mL）的C阈值，尤其是在大量患者和更同质的癌症类型中。然而，这些结果支持在肿瘤学中对依维莫司进行TDM。
