Cooney Matthew M, Radivoyevitch Tomas, Dowlati Afshin, Overmoyer Beth, Levitan Nathan, Robertson Kelly, Levine Sandra L, DeCaro Kathleen, Buchter Carol, Taylor Anne, Stambler Bruce S, Remick Scot C
Division of Hematology, Department of Medicine, Case Western Reserve University (CWRU), School of Medicine, Cleveland, Ohio, USA.
Clin Cancer Res. 2004 Jan 1;10(1 Pt 1):96-100. doi: 10.1158/1078-0432.ccr-0364-3.
The purpose of our study was to review and determine the cardiovascular safety profile of combretastatin A4 phosphate (CA4P) in a Phase I study in 25 patients with advanced solid tumors.
CA4P was administered in a dose-escalating fashion starting at 18 mg/m(2) i.v. every 21 days, and the maximal dosage was 90 mg/m(2). Continuous evaluation included bedside blood pressure and pulse monitoring, 12-lead electrocardiogram (ECG) at fixed time points for measured QT interval determination, determination of the corrected QT interval (QTc) using Bazett's formula QTc = QT/(R-R interval)(1/2), and chart review. Pharmacodynamic correlations of CA4P dose, CA4P/CA4 area under the curve, and C(max) versus heart rate (HR), blood pressure, QT, and QTc intervals, over the first 4 h postdosing were analyzed.
After CA4P administration, there were significant increases in QTc interval at the 3-h and 4-h time points [27.2 ms (P < 0.0001) and 30.8 ms (P < 0.0001), respectively] and HR at the 3- and 4-h time points [13.2 beats per minute (bpm; P < 0.01) and 15.1 bpm (P < 0.001), respectively]. Three of 25 patients had prolonged QTc intervals at baseline, whereas 15 (60%) of 25 and 18 (75%) of 24 patients had prolonged QTc intervals at 3 and 4 h. The slope of HR and QTc increasing as a function of time during the first 4 h was correlated to dose (in milligrams) of CA4P (P = 0.01 and r = 0.49 for HR, P = 0.005 and r = 0.55 for QTc) and to CA4 area under the curve (P = 0.04 and r = 0.41 for HR, P = 0.02 and r = 0.44 for QTc); blood pressure and uncorrected QTc interval dose-response correlations were not significant. Two patients had ECG changes consistent with an acute coronary syndrome within 24 h of CA4P infusion.
CA4P prolongs the QTc interval. There was a temporal relationship with the CA4P infusion and with ECG changes consistent with an acute coronary syndrome in two patients. It is advisable that future trials with CA4P have eligibility guidelines limiting patients with known coronary artery disease or those with multiple coronary artery disease risk factors until more experience is gained regarding potential cardiovascular toxicity with this agent.
我们研究的目的是在一项针对25例晚期实体瘤患者的I期研究中，回顾并确定磷酸考布他汀A4（CA4P）的心血管安全性。
CA4P采用剂量递增方式给药，起始剂量为18mg/m²静脉注射，每21天一次，最大剂量为90mg/m²。持续评估包括床边血压和脉搏监测、在固定时间点进行12导联心电图（ECG）以测定QT间期、使用Bazett公式QTc = QT/(R-R间期)(1/2)测定校正QT间期（QTc）以及病历审查。分析给药后前4小时内CA4P剂量、CA4P/CA4曲线下面积和Cmax与心率（HR）、血压、QT和QTc间期之间的药效学相关性。
给予CA4P后，3小时和4小时时间点的QTc间期显著增加[分别为27.2毫秒（P < 0.0001）和30.8毫秒（P < 0.0001）]以及3小时和4小时时间点的HR显著增加[分别为每分钟13.2次心跳（bpm；P < 0.01）和15.1 bpm（P < 0.001）]。25例患者中有3例在基线时QTc间期延长，而25例中有15例（60%）和24例中有18例（75%）在3小时和4小时时QTc间期延长。给药后前4小时内HR和QTc随时间增加的斜率与CA4P的剂量（毫克）相关（HR的P = 0.01，r = 0.49；QTc的P = 0.005，r = 0.55）以及与CA4曲线下面积相关（HR的P = 0.04，r = 0.41；QTc的P = 0.02，r = 0.44）；血压和未校正QT间期与剂量的反应相关性不显著。两名患者在输注CA4P后24小时内出现与急性冠状动脉综合征一致的ECG变化。
CA4P可延长QTc间期。输注CA4P与两名患者出现与急性冠状动脉综合征一致的ECG变化之间存在时间关系。建议未来进行CA4P试验时制定入选标准，限制已知患有冠状动脉疾病或有多种冠状动脉疾病危险因素的患者入组，直到对该药物潜在的心血管毒性有更多经验。
