Bailey Hanna, McPherson Jordan P, Bailey Erin B, Werner Theresa L, Gupta Sumati, Batten Julia, Reddy Guru, Bhat Gajanan, Sharma Sunil, Agarwal Neeraj
Huntsman Cancer Institute, The University of Utah, 2000 Circle of Hope, Ste 2123, Salt Lake City, UT, 84112, USA.
Spectrum Pharmaceuticals, Irvine, CA, USA.
Cancer Chemother Pharmacol. 2016 Nov;78(5):1059-1071. doi: 10.1007/s00280-016-3167-7. Epub 2016 Oct 15.
Belinostat is an inhibitor of histone deacetylase enzymes, resulting in DNA repair inhibition and apoptosis. Present data are lacking to provide dosing recommendations in renal insufficiency. The purpose of this trial was to assess the pharmacokinetics (PK) of belinostat and belinostat metabolites in plasma and urine.
This was a phase I, single-center, open-label, two-part study. In Part I, patients received single-agent belinostat 1000 mg/m. Blood and urine samples were collected at pre-specified time points to determine PK of belinostat and metabolites and their elimination in urine. In Part II, patients were permitted to continue belinostat in 21-day cycles on Days 1 through 5 until disease progression, unacceptable toxicity, or according to patient preference.
A total of nine patients with advanced solid tumors were treated. Median t for belinostat was observed 10 min after the start of infusion. Concentrations of belinostat rapidly declined with a t of 2.9 h. The mean fraction of belinostat excreted unchanged in urine was 0.926 %. The metabolites belinostat glucuronide and 3-ASBA represented the largest fractions of belinostat dose excreted in urine (30.5 and 4.61 %, respectively), while renal excretion appeared to be a minor route of elimination for the parent belinostat (<1 %). The most common adverse events were nausea, fatigue, and diarrhea. One Grade 3 adverse event (constipation) was thought to be treatment related.
Urinary elimination of parent belinostat was minimal, although a combined 36.7 % of belinostat metabolites were excreted in urine. Since these metabolites are primarily inactive, belinostat may not require dosage adjustment in renal dysfunction.
贝利司他是一种组蛋白脱乙酰酶抑制剂，可导致DNA修复抑制和细胞凋亡。目前缺乏在肾功能不全患者中提供给药建议的数据。本试验的目的是评估贝利司他及其代谢产物在血浆和尿液中的药代动力学（PK）。
这是一项I期、单中心、开放标签的两部分研究。在第一部分中，患者接受单药贝利司他1000mg/m²。在预先指定的时间点采集血液和尿液样本，以确定贝利司他及其代谢产物的PK及其在尿液中的消除情况。在第二部分中，允许患者在第1天至第5天每21天一个周期继续使用贝利司他，直至疾病进展、出现不可接受的毒性或根据患者意愿停药。
共治疗了9例晚期实体瘤患者。输注开始后10分钟观察到贝利司他的中位tmax。贝利司他浓度迅速下降，t1/2为2.9小时。贝利司他以原形经尿液排泄的平均比例为0.926%。代谢产物贝利司他葡糖醛酸和3-ASBA是经尿液排泄的贝利司他剂量中占比最大的部分（分别为30.5%和4.61%），而肾脏排泄似乎是母体贝利司他的次要消除途径（<1%）。最常见的不良事件是恶心、疲劳和腹泻。1例3级不良事件（便秘）被认为与治疗有关。
母体贝利司他经尿液排泄极少，尽管贝利司他代谢产物合计有36.7%经尿液排泄。由于这些代谢产物主要无活性，贝利司他在肾功能不全时可能无需调整剂量。
