Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors
Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors
复制标题
DOI：
10.1200/jco.2007.14.0988
复制
发表时间：
2008-04-01
影响因子：
45.3
通讯作者：
Judson, Ian
中科院分区：
文献类型：
--
作者：
O'Donnell, Anne;Faivre, Sandrine;Judson, Ian
目的筛选雷帕霉素靶向抑制剂依维莫司（RAD 0 0 1）的最佳给药方案和剂量。方法对晚期癌症患者口服依维莫司（5 ~ 30 mg/wk）进行剂量递增研究，并进行药代动力学（PK）和药效学（PD）研究。PD数据提示调查50和70毫克每周和每日给药5和10毫克。结果92例患者接受治疗。在50 mg/wk（口腔炎和疲劳）和10 mg/d（高血糖症）剂量组各有1例患者出现剂量限制性毒性;因此，未达到最大耐受剂量。在剂量>= 20 mg/wk时，外周血单核细胞中S6激酶1活性至少被抑制7天。曲线下面积与剂量成比例增加，但在剂量>= 20 mg/wk时，最大血清浓度的增加低于比例增加。终末半衰期为30小时（范围：26 - 38小时）。部分反应，观察4例，12例患者保持无进展>= 6 months，包括5 10例肾细胞cancer.Conclusion依维莫司是令人满意的耐受剂量高达70 mg/wk和10 mg/d与可预测的PK。肿瘤中的抗肿瘤活性和PD需要进一步的临床研究。推荐20 mg/wk和5 mg/d的剂量作为这些研究的适当起始剂量。
Purpose To identify the optimal regimen and dosage of the oral mammalian target of rapamycin inhibitor everolimus (RAD001).Methods We performed a dose-escalation study in advanced cancer patients administering oral everolimus 5 to 30 mg/wk, with pharmacokinetic (PK) and pharmacodynamic (PD) studies. PD data prompted investigation of 50 and 70 mg weekly and daily dosing at 5 and 10 mg.Results Ninety-two patients were treated. Dose-limiting toxicity was seen in one patient each at 50 mg/wk (stomatitis and fatigue) and 10 mg/d (hyperglycemia); hence, the maximum-tolerated dose was not reached. S6 kinase 1 activity in peripheral-blood mononuclear cells was inhibited for at least 7 days at doses >= 20 mg/wk. Area under the curve increased proportional to dose, but maximum serum concentration increased less than proportionally at doses >= 20 mg/wk. Terminal half- life was 30 hours (range, 26 to 38 hours). Partial responses were observed in four patients, and 12 patients remained progression free for >= 6 months, including five of 10 patients with renal cell carcinoma.Conclusion Everolimus was satisfactorily tolerated at dosages up to 70 mg/wk and 10 mg/d with predictable PK. Antitumor activity and PD in tumors require further clinical investigation. Doses of 20 mg/wk and 5 mg/d are recommended as appropriate starting doses for these studies.