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首页> 外文期刊>EBioMedicine >A Phase I Safety, Pharmacokinetic, and Pharmacodynamic Presurgical Trial of Vitamin E @d-tocotrienol in Patients with Pancreatic Ductal Neoplasia
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A Phase I Safety, Pharmacokinetic, and Pharmacodynamic Presurgical Trial of Vitamin E @d-tocotrienol in Patients with Pancreatic Ductal Neoplasia

机译：胰腺导管癌患者中维生素E @ d-生育三烯酚的I期安全性，药代动力学和药理动力学术前试验

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Background: Vitamin E @d-tocotrienol (VEDT), a natural vitamin E from plants, has shown anti-neoplastic and chemoprevention activity in preclinical models of pancreatic cancer. Here, we investigated VEDT in patients with pancreatic ductal neoplasia in a window-of-opportunity preoperative clinical trial to assess its safety, tolerability, pharmacokinetics, and apoptotic activity. Methods: Patients received oral VEDT at escalating doses (from 200 to 3200mg) daily for 13days before surgery and one dose on the day of surgery. Dose escalation followed a three-plus-three trial design. Our primary endpoints were safety, VEDT pharmacokinetics, and monitoring of VEDT-induced neoplastic cell apoptosis (ClinicalTrials.gov number NCT00985777). Findings: In 25 treated patients, no dose-limiting toxicity was encountered; thus no maximum-tolerated dose was reached. One patient had a drug-related adverse event (diarrhea) at a 3200-mg daily dose level. The effective half-life of VEDT was ~4h. VEDT concentrations in plasma and exposure profiles were quite variable but reached levels that are bioactive in preclinical models. Biological activity, defined as significant induction of apoptosis in neoplastic cells as measured by increased cleaved caspase-3 levels, was seen in the majority of patients at the 400-mg to 1600-mg daily dose levels. Interpretation: VEDT from 200 to 1600mg daily taken orally for 2weeks before pancreatic surgery was well tolerated, reached bioactive levels in blood, and significantly induced apoptosis in the neoplastic cells of patients with pancreatic ductal neoplasia. These promising results warrant further clinical investigation of VEDT for chemoprevention and/or therapy of pancreatic cancer.
机译：背景：维生素E d-生育三烯酚（VEDT）是一种来自植物的天然维生素E，在胰腺癌的临床前模型中已显示出抗肿瘤和化学预防的活性。在这里，我们在一个机会性的术前临床试验中对胰腺导管癌的患者进行了VEDT调查，以评估其安全性，耐受性，药代动力学和凋亡活性。方法：患者在手术前13天每天接受递增剂量的口服VEDT（200至3200mg），并在手术当天接受一剂。剂量递增遵循三加三项试验设计。我们的主要研究终点是安全性，VEDT药代动力学和监测VEDT诱导的赘生性细胞凋亡（ClinicalTrials.gov编号NCT00985777）。结果：在25例接受治疗的患者中，未遇到剂量限制性毒性。因此没有达到最大耐受剂量。一名患者在每天3200 mg的剂量水平上发生过与药物相关的不良事件（腹泻）。 VEDT的有效半衰期约为4h。血浆和暴露曲线中的VEDT浓度变化很大，但达到临床前模型中具有生物活性的水平。生物学活性被定义为肿瘤细胞凋亡的显着诱导，这是通过裂解caspase-3水平的增加来衡量的，在大多数患者中，每日剂量为400 mg至1600 mg。解释：胰腺手术前2周，每天口服200至1600mg VEDT具有良好的耐受性，达到血液中的生物活性水平，并显着诱导了胰腺导管肿瘤患者的肿瘤细胞凋亡。这些有希望的结果保证了对VEDT进行胰腺癌化学预防和/或治疗的进一步临床研究。

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