Pfizer Inc, 500 Arcola Road, Collegeville, PA 19426, USA.
Cancer Chemother Pharmacol. 2012 Jun;69(6):1433-42. doi: 10.1007/s00280-012-1845-7. Epub 2012 Feb 26.
Temsirolimus, a selective inhibitor of mammalian target of rapamycin, is an approved treatment for patients with advanced renal cell carcinoma (RCC). This study assessed the effect of intravenous (i.v.) temsirolimus 25 mg, the recommended dose for patients with RCC, on the corrected QT (QTc) interval.
This 3-period crossover study enrolled healthy subjects. In periods 1 and 2, subjects received i.v. placebo either alone or with open-label oral moxifloxacin. In period 3, subjects received a single dose of temsirolimus 25 mg. The primary statistical objective was to estimate the effect of temsirolimus compared with placebo on change from time-matched baseline QTc at the end of infusion (0.5 h). Assay sensitivity was evaluated by the effect of moxifloxacin on change from time-matched baseline QTc compared with placebo.
In total, 58 subjects were enrolled. Temsirolimus had no effect on QTc interval in the primary analysis. At 11 of 12 secondary time points, the upper bound for the temsirolimus QTc 90% confidence intervals for the time-matched change from baseline difference from placebo was <10 ms, with no evidence of QTc trends or relationship to concentrations of temsirolimus or its major metabolite, sirolimus. Moxifloxacin, the positive control, produced a significant increase in the QTc interval compared with placebo 0.5-4 h post-dose (P < 0.0001). No subject had a QTc interval exceeding 450 ms or a change from baseline of >30 ms.
Therapeutic exposure to temsirolimus is not associated with clinically significant changes in QTc intervals in healthy adults.
依维莫司是一种哺乳动物雷帕霉素靶蛋白的选择性抑制剂，已被批准用于治疗晚期肾细胞癌（RCC）患者。本研究评估了静脉注射（IV）推荐剂量的依维莫司 25mg 对校正 QT（QTc）间期的影响。
这是一项 3 期交叉研究，纳入了健康受试者。在第 1 期和第 2 期，受试者分别单独接受 IV 安慰剂或与开放标签的口服莫西沙星联合用药。在第 3 期，受试者接受单次剂量的依维莫司 25mg。主要的统计目的是评估与安慰剂相比，依维莫司对输注结束时（0.5h）与时间匹配的基线 QTc 变化的影响。通过与安慰剂相比，莫西沙星对与时间匹配的基线 QTc 变化的影响来评估检测灵敏度。
共纳入 58 名受试者。依维莫司对 QTc 间期无影响。在 12 个次要时间点中的 11 个时间点，与安慰剂相比，依维莫司 QTc90%置信区间的时间匹配从基线差异的上限<10ms，没有 QTc 趋势或与依维莫司及其主要代谢物西罗莫司浓度相关的证据。阳性对照莫西沙星与安慰剂相比，在给药后 0.5-4h 时 QTc 间隔明显增加（P<0.0001）。没有受试者的 QTc 间隔超过 450ms 或从基线变化超过 30ms。
在健康成年人中，依维莫司的治疗暴露与 QTc 间期的临床显著变化无关。
