Department of Pharmacy, University Hospital Doctor Peset of Valencia, Valencia, Spain.
Foundation for the Promotion of Health and Biomedical Research of Valencia (FISABIO), Valencia, Spain.
Basic Clin Pharmacol Toxicol. 2018 Jul;123(1):65-71. doi: 10.1111/bcpt.12977. Epub 2018 Mar 30.
The quantification of enzyme activity in the patient treated with enzyme replacement therapy (ERT) has been suggested as a tool for dosage individualization, so we conducted a study to evaluate the relationship between glucocerebrosidase activity and clinical response in patients with Gaucher disease type I (GD1) to ERT. The study included patients diagnosed with GD1, who were being treated with ERT, and healthy individuals. Markers based on glucocerebrosidase activity measurement in patients' leucocytes were studied: enzyme activity at 15 min. post-infusion (Act ) reflects the amount of enzyme that is distributed in the body post-ERT infusion, and accumulated glucocerebrosidase activity during ERT infusion (Act ) indicates the total drug exposure during infusion. The clinical response was evaluated based on criteria established by Pastores et al. and Gaucher Severity Score Index. Statistical analysis included ROC analysis and area under the curve test. Act and Act were found to be moderate predictive markers of an optimal clinical response (area under the ROC of Act was 0.733 and Act was 0.817). Act showed statistical significance in its discriminative capacity (p < 0.05) for obtaining an optimal response to ERT. The cut-off point was 58% (RR = 1.800; 95% CI: 1.003-3.229; p < 0.05). Moreover, Act showed a significant and inverse correlation with the Gaucher Severity Score Index, and Act and Act presented a significant correlation with residual enzyme activity at diagnosis. Markers based on glucocerebrosidase activity have a good correlation with clinical response to ERT. Therefore, it could provide supporting clinical data for dose management in GD1 patients.
我们进行了一项研究，以评估葡萄糖脑苷脂酶（GCase）活性与接受酶替代疗法（ERT）治疗的 I 型戈谢病（GD1）患者的临床反应之间的关系，该研究建议将患者接受 ERT 治疗时的酶活性量化作为剂量个体化的工具。该研究纳入了正在接受 ERT 治疗的 GD1 患者和健康对照者。研究了基于患者白细胞中 GCase 活性测量的标志物：输注后 15 分钟的酶活性（Act）反映了 ERT 输注后分布在体内的酶量，而 ERT 输注期间累积的葡萄糖脑苷脂酶活性（Act）则反映了输注期间的总药物暴露量。临床反应根据 Pastores 等人和 Gaucher 严重程度评分指数（Gaucher Severity Score Index，GSSI）制定的标准进行评估。统计分析包括 ROC 分析和曲线下面积（area under the curve，AUC）检验。Act 和 Act 被发现是最佳临床反应的中等预测标志物（Act 的 ROC 曲线下面积为 0.733，Act 的 AUC 为 0.817）。Act 在其区分能力上具有统计学意义（p<0.05），可以获得 ERT 的最佳反应。截断值为 58%（RR=1.800；95%CI：1.003-3.229；p<0.05）。此外，Act 与 GSSI 呈显著负相关，Act 和 Act 与诊断时残留酶活性呈显著正相关。基于 GCase 活性的标志物与 ERT 的临床反应具有良好的相关性。因此，它可以为 GD1 患者的剂量管理提供支持临床的数据。
