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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Exposure-Response Analysis of Sonidegib (LDE225), an Oral Inhibitor of the Hedgehog Signaling Pathway, for Effectiveness and Safety in Patients With Advanced Solid Tumors
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Exposure-Response Analysis of Sonidegib (LDE225), an Oral Inhibitor of the Hedgehog Signaling Pathway, for Effectiveness and Safety in Patients With Advanced Solid Tumors

机译：Sonidegib（LDE225）（一种刺猬信号通路的口服抑制剂）的暴露-响应分析对晚期实体瘤患者的有效性和安全性

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Sonidegib selectively inhibits smoothened protein, suppresses the growth of Hedgehog pathway-dependent tumors, and has recently been approved in the indication of locally advanced basal cell carcinoma. A comprehensive exposure-response analysis was conducted to further characterize the relationship of sonidegib exposure to efficacy and safety. Minimum observed plasma concentration at predose (C-min), peak concentration (C-max), and area under the curve were used as exposure endpoints. Exposure-efficacy analyses included data from 190 patients who received sonidegib 200mg or 800 mg once daily in the primary efficacy study. Objective response rate (ORR) (complete response [CR] or partial response [PR]), progression-free survival (PFS), and time to tumor response (TTR) were assessed by logistic regression, Cox regression, and Kaplan-Meier analyses. Exposure-safety (creatine phosphokinase [CK] elevation) analyses included data from 336 patients pooled from 4 clinical trials and included doses across ranges of 100 to 3000 mg once daily and 250 to 750mg twice daily. Similar plasma exposure was observed between responders and nonresponders. The logistic regression model of week 5 C-min vs ORR indicated no relationship between sonidegib exposure resulting from 200mg or 800 mg doses and the probability of CR or PR. A similar conclusion of no exposure-efficacy relationship was drawn from the PFS and TTR analyses. Increased exposure was associated with a greater risk of grade 3 or 4 CK elevation, with lower risk in females than in males when C-min was used in the model. These analyses support the sonidegib dose recommendation for registration and are consistent with clinical observations.
机译：Sonidegib选择性抑制平滑化的蛋白质，抑制Hedgehog途径依赖性肿瘤的生长，最近已被批准用于局部晚期基底细胞癌的适应症。进行了全面的暴露-反应分析，以进一步表征sonidegib暴露与疗效和安全性之间的关系。给药前观察到的最低血浆浓度（C-min），峰浓度（C-max）和曲线下面积用作暴露终点。暴露功效分析包括来自190名患者的数据，这些患者在主要功效研究中每天接受200 mg或800 mg的Sonidegib一次。通过逻辑回归，Cox回归和Kaplan-Meier分析评估了客观缓解率（ORR）（完全缓解[CR]或部分缓解[PR]），无进展生存期（PFS）和到达肿瘤的时间（TTR）。 。暴露安全性（肌酸磷酸激酶[CK]升高）分析包括来自4个临床试验的336名患者的数据，包括每日一次100至3000 mg和每天两次250至750 mg的剂量。在反应者和非反应者之间观察到相似的血浆暴露。第5周C-min与ORR的逻辑回归模型表明，200mg或800mg剂量的sonidegib暴露与CR或PR的可能性之间没有关系。从PFS和TTR分析得出类似的结论，即没有暴露-功效关系。当在模型中使用C-min时，暴露增加与3级或4级CK升高的风险较高相关，女性的风险低于男性。这些分析支持sonidegib推荐的注册剂量，并与临床观察结果一致。

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