Department of Thoracic/Head and Neck Medical Oncology, Unit 432, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA.
Cancer. 2010 Mar 15;116(6):1582-91. doi: 10.1002/cncr.24927.
The recently developed the Src and Abelson (Abl) kinase inhibitor dasatinib has antitumor effects in epithelial and mesenchymal tumors. Preclinical data have indicated that dasatinib is metabolized primarily through cytochrome P450 3A4 (CYP3A4) and may cause QT prolongation. In light of its improved tolerability, the authors were interested in the safety of a once-daily dasatinib regimen.
The authors conducted a phase 1 trial of dasatinib in 29 patients with advanced solid tumors. Segment 1 of the trial was short term and sequential and was designed to determine whether the coadministration of the potent CYP3A4 inhibitor ketoconazole had an effect on the pharmacokinetics of dasatinib. Segment 2 was designed to evaluate the safety of dasatinib as dosing was increased. QT intervals were monitored closely in both segments. Efficacy was assessed in Segment 2 using both positron emission tomography and computed tomography.
Hematologic toxicities were markedly less than those observed in patients with leukemia, whereas nonhematologic toxicities were similar. The authors determined that the maximum recommended dose was 180 mg once daily based on the incidence of pleural effusion. Coadministration of ketoconazole led to a marked increase in dasatinib exposure, which was correlated with an increase in corrected QT (QTc) values of approximately 6 msec. No adverse cardiac events were observed.
The dose-limiting toxic effect for dasatinib was pleural effusion. The pharmacokinetic and cardiac studies indicated that coadministration of dasatinib with potent CYP3A4 inhibitors or agents that prolong the QTc interval should be avoided if possible. Close monitoring for toxicity and dose reduction should be considered if the coadministration of such agents cannot be avoided.
最近开发的Src 和 Abelson（Abl）激酶抑制剂 dasatinib 在上皮和间充质肿瘤中具有抗肿瘤作用。临床前数据表明，dasatinib 主要通过细胞色素 P450 3A4（CYP3A4）代谢，可能导致 QT 延长。鉴于其改善的耐受性，作者对每日一次 dasatinib 方案的安全性感兴趣。
作者对 29 例晚期实体瘤患者进行了 dasatinib 的 I 期试验。试验的第 1 部分是短期的和连续的，旨在确定强 CYP3A4 抑制剂酮康唑的联合用药是否会影响 dasatinib 的药代动力学。第 2 部分旨在评估增加剂量时 dasatinib 的安全性。在这两个部分中都密切监测 QT 间期。第 2 部分使用正电子发射断层扫描和计算机断层扫描评估疗效。
血液学毒性明显低于白血病患者，而非血液学毒性相似。作者根据胸腔积液的发生率确定最大推荐剂量为 180mg 每日一次。酮康唑的联合用药导致 dasatinib 暴露量显著增加，这与校正 QT（QTc）值增加约 6msec 相关。未观察到不良心脏事件。
dasatinib 的剂量限制毒性作用是胸腔积液。药代动力学和心脏研究表明，如果可能，应避免 dasatinib 与强效 CYP3A4 抑制剂或延长 QTc 间隔的药物联合用药。如果不能避免联合使用这些药物，则应密切监测毒性和剂量减少。
