Pfizer Global Research and Development, New York, New York, USA.
Clin Cancer Res. 2009 Nov 15;15(22):7045-52. doi: 10.1158/1078-0432.CCR-09-1521. Epub 2009 Nov 10.
To evaluate the effects of sunitinib, a multitargeted tyrosine kinase inhibitor, on the QT interval in patients with cancer.
Patients received sunitinib loading doses (150-200 mg) on days 3 and 9 and maintenance doses (50 mg/d) on days 4 to 8. Moxifloxacin (day 1), placebo (day 2), and granisetron [with placebo (day 2) or sunitinib (days 3 and 9)] were also administered. Treatment effects were evaluated by time-matched, serial electrocardiograms, and manually overread.
Twenty-four of 48 patients were QT/PK evaluable. Moxifloxacin produced a time-matched, maximum mean placebo-adjusted corrected QT interval (QT(c)F) of 5.6 ms [90% confidence interval (CI), 1.9-9.3]. Sunitinib QT(c)F changes correlated with exposure, but not T(max). Maximum mean time-matched, placebo-adjusted QT(c)F was 9.6 ms (90% CI, 4.1-15.1) at steady state/therapeutic concentrations (day 3) and 15.4 ms (90% CI, 8.4-22.4) at supratherapeutic concentrations (day 9). No patient had a QT(c)F >500 ms. Concomitant granisetron produced no significant QT(c)F prolongation. Sunitinib-related adverse events were as previously described.
Sunitinib has a dose-dependent effect on QT interval. The increased risk of ventricular arrhythmias must be weighed against the therapeutic benefit sunitinib provides to patients with advanced cancer.
评估多靶点酪氨酸激酶抑制剂舒尼替尼对癌症患者 QT 间期的影响。
患者在第 3 天和第 9 天接受舒尼替尼负荷剂量（150-200mg），在第 4 天至第 8 天接受维持剂量（50mg/d）。第 1 天给予莫西沙星、第 2 天给予安慰剂、第 2 天和第 3 天及第 9 天给予格拉司琼[同时给予安慰剂（第 2 天）或舒尼替尼（第 3 天和第 9 天）]。通过时间匹配的连续心电图和手动复查来评估治疗效果。
48 例患者中有 24 例可进行 QT/PK 评估。莫西沙星产生了时间匹配的最大平均安慰剂校正 QT 间期（QTcF）变化 5.6ms[90%置信区间（CI）为 1.9-9.3]。舒尼替尼的 QTcF 变化与暴露量相关，但与 Tmax 无关。在稳态/治疗浓度（第 3 天）时，最大平均时间匹配的安慰剂校正 QTcF 为 9.6ms（90%CI 为 4.1-15.1），在超治疗浓度（第 9 天）时为 15.4ms（90%CI 为 8.4-22.4）。没有患者的 QTcF>500ms。同时给予格拉司琼不会导致 QTcF 显著延长。舒尼替尼相关的不良反应与之前的报道一致。
舒尼替尼对 QT 间期有剂量依赖性影响。必须权衡舒尼替尼对晚期癌症患者的治疗益处与室性心律失常的风险。
