Departments of Medicine, University of Chicago, Chicago, IL 60637, USA.
Clin Cancer Res. 2012 Sep 1;18(17):4785-93. doi: 10.1158/1078-0432.CCR-12-0110. Epub 2012 Aug 7.
Sirolimus is the eponymous inhibitor of the mTOR; however, only its analogs have been approved as cancer therapies. Nevertheless, sirolimus is readily available, has been well studied in organ transplant patients, and shows efficacy in several preclinical cancer models.
Three simultaneously conducted phase I studies in advanced cancer patients used an adaptive escalation design to find the dose of oral, weekly sirolimus alone or in combination with either ketoconazole or grapefruit juice that achieves similar blood concentrations as its intravenously administered and approved prodrug, temsirolimus. In addition, the effect of sirolimus on inhibition of p70S6 kinase phosphorylation in peripheral T cells was determined.
Collectively, the three studies enrolled 138 subjects. The most commonly observed toxicities were hyperglycemia, hyperlipidemia, and lymphopenia in 52%, 43%, and 41% of subjects, respectively. The target sirolimus area under the concentration curve (AUC) of 3,810 ng-h/mL was achieved at sirolimus doses of 90, 16, and 25 mg in the sirolimus alone, sirolimus plus ketoconazole, and sirolimus plus grapefruit juice studies, respectively. Ketoconazole and grapefruit juice increased sirolimus AUC approximately 500% and 350%, respectively. Inhibition of p70 S6 kinase phosphorylation was observed at all doses of sirolimus and correlated with blood concentrations. One partial response was observed in a patient with epithelioid hemangioendothelioma.
Sirolimus can be feasibly administered orally, once weekly with a similar toxicity and pharmacokinetic profile compared with other mTOR inhibitors and warrants further evaluation in studies of its comparative effectiveness relative to recently approved sirolimus analogs.
西罗莫司是 mTOR 的同名抑制剂；然而，只有它的类似物被批准用于癌症治疗。尽管如此，西罗莫司很容易获得，在器官移植患者中得到了充分的研究，并在几种临床前癌症模型中显示出疗效。
在晚期癌症患者中同时进行的三项 I 期研究采用适应性递增设计，以确定单独口服西罗莫司或与酮康唑或葡萄柚汁联合使用的剂量，以达到与其静脉内给予和批准的前药替西罗莫司相似的血药浓度。此外，还确定了西罗莫司对抑制外周 T 细胞中 p70S6 激酶磷酸化的作用。
这三项研究共纳入了 138 名患者。最常见的毒性反应是 52%、43%和 41%的患者分别出现高血糖、高血脂和淋巴细胞减少。西罗莫司单独、西罗莫司加酮康唑和西罗莫司加葡萄柚汁研究中，西罗莫司的目标 AUC 分别为 3810ng-h/mL，西罗莫司剂量为 90、16 和 25mg。酮康唑和葡萄柚汁使西罗莫司 AUC 分别增加约 500%和 350%。在所有西罗莫司剂量下均观察到 p70S6 激酶磷酸化的抑制作用，与血药浓度相关。一名上皮样血管内皮细胞瘤患者出现部分缓解。
西罗莫司可以口服给药，每周一次，与其他 mTOR 抑制剂相比具有相似的毒性和药代动力学特征，值得进一步评估其与最近批准的西罗莫司类似物的相对疗效。
