Karovic S, Wen Y, Karrison T G, Bakris G L, Levine M R, House L K, Wu K, Thomeas V, Rudek M A, Wright J J, Cohen E E W, Fleming G F, Ratain M J, Maitland M L
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, Illinois, USA.
Clin Pharmacol Ther. 2014 Jul;96(1):27-35. doi: 10.1038/clpt.2014.63. Epub 2014 Mar 17.
Hypertension after treatment with vascular endothelial growth factor (VEGF) receptor inhibitors is associated with superior treatment outcomes for advanced cancer patients. To determine whether increased sorafenib doses cause incremental increases in blood pressure (BP), we measured 12-h ambulatory BP in 41 normotensive advanced solid tumor patients in a randomized dose-escalation study. After 7 days' treatment (400 mg b.i.d.), mean diastolic BP (DBP) increased in both study groups. After dose escalation, group A (400 mg t.i.d.) had marginally significant further increase in 12-h mean DBP (P = 0.053), but group B (600 mg b.i.d.) did not achieve statistically significant increases (P = 0.25). Within groups, individuals varied in BP response to sorafenib dose escalation, but these differences did not correlate with changes in steady-state plasma sorafenib concentrations. These findings in normotensive patients suggest BP is a complex pharmacodynamic biomarker of VEGF inhibition. Patients have intrinsic differences in sensitivity to sorafenib's BP-elevating effects.
血管内皮生长因子（VEGF）受体抑制剂治疗后出现的高血压与晚期癌症患者更好的治疗结果相关。为了确定增加索拉非尼剂量是否会导致血压（BP）逐步升高，我们在一项随机剂量递增研究中测量了41例血压正常的晚期实体瘤患者的12小时动态血压。治疗7天（400mg，每日两次）后，两个研究组的平均舒张压（DBP）均升高。剂量递增后，A组（400mg，每日三次）的12小时平均DBP进一步小幅显著升高（P = 0.053），但B组（600mg，每日两次）未实现统计学显著升高（P = 0.25）。在组内，个体对索拉非尼剂量递增的血压反应各不相同，但这些差异与稳态血浆索拉非尼浓度的变化无关。血压正常患者的这些发现表明，血压是VEGF抑制的一个复杂的药效学生物标志物。患者对索拉非尼升高血压作用的敏感性存在内在差异。
