Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, 84112, UT, USA.
Spectrum Pharmaceuticals, Irvine, CA, USA.
Cancer Chemother Pharmacol. 2016 Feb;77(2):299-308. doi: 10.1007/s00280-015-2934-1. Epub 2015 Dec 30.
Belinostat is a potent small molecule inhibitor that exerts its antitumor effect through inhibition of histone deacetylase. The purpose of this study was to evaluate the pharmacokinetics and pharmacodynamics of warfarin (as a reference drug metabolized by CYP2C9) in the presence and absence of belinostat.
We conducted a phase I, single-center, open-label, drug-drug interaction study between belinostat and warfarin. In part I, patients were given warfarin 5 mg orally (day-14 and 3) and belinostat 1000 mg/m(2) (days 1 through 5). Patients receiving benefit continued belinostat on days 1 through 5 every 21 days until disease progression, unacceptable toxicity, or per patient preference.
A total of 18 patients were treated. With belinostat, the least-squared means for maximum concentration (C max), area under the curve0-∞, and area under the curve0-t of R-warfarin were slightly increased. However, for the more potent S-warfarin isomer, the same parameters were primarily contained within the pre-specified equivalence limits of 0.80 and 1.25, indicating there was no statistically significant interaction between S-warfarin and belinostat. The most common adverse events were nausea, vomiting, and fatigue. Three grade 3 adverse events (diarrhea 5.6 %, nausea 5.6 %, and vomiting 5.6 %) were thought to be treatment related. Progression-free survival ranged from 0.2 to 13.8 months in all patients.
Belinostat did not significantly affect the pharmacokinetics and pharmacodynamics of warfarin, indicating no clinically relevant effect on the enzymatic activity of CYP2C9.
贝林司他是一种有效的小分子抑制剂，通过抑制组蛋白去乙酰化酶发挥其抗肿瘤作用。本研究旨在评估贝林司他存在和不存在时华法林（一种被 CYP2C9 代谢的参考药物）的药代动力学和药效学。
我们进行了一项单中心、开放标签、药物相互作用的 I 期研究，比较了贝林司他和华法林。在 I 部分，患者分别于第 14 天和第 3 天口服华法林 5mg，并于第 1 天至第 5 天接受贝林司他 1000mg/m²。受益患者继续接受贝林司他治疗，每 21 天一次，直至疾病进展、不可接受的毒性或根据患者意愿。
共治疗了 18 例患者。与贝林司他合用时，R-华法林的最大浓度（C max）、曲线下面积 0-∞和曲线下面积 0-t 的最小二乘均值略有增加。然而，对于更有效的 S-华法林异构体，相同的参数主要包含在 0.80 和 1.25 的预定等效限内，表明 S-华法林与贝林司他之间无统计学显著相互作用。最常见的不良反应为恶心、呕吐和疲劳。3 例 3 级不良事件（腹泻 5.6%、恶心 5.6%和呕吐 5.6%）被认为与治疗相关。所有患者的无进展生存期为 0.2 至 13.8 个月。
贝林司他对华法林的药代动力学和药效学无显著影响，表明对 CYP2C9 的酶活性无临床相关影响。
