BIOEQUIVALENCE COMBINATION 776C85/5FU PILL & INDIVIDUAL 776C85 & 5FU PILL

目的：本I期研究旨在确定联合化疗药物776 C85/5-FU的片剂与单独776 C85和5-FU片剂的生物等效性。复方片剂的优点包括减少患者接受776 C85和标准剂量FU的机会，这可能导致致命毒性。它使患者更容易服用药物，并确保患者在没有776 C85的情况下不服用口服5-FU。在临床前和早期临床研究中，776 C85显著增加了口服5-FU的生物利用度和半衰期，降低了口服5-FU的药代动力学变异性。在啮齿动物肿瘤模型中，它还增加了5-FU的抗肿瘤疗效，并将5-FU的治疗指数增加了6倍。研究方法：这是一项在36例患者中进行的随机、开放标签、3向交叉研究，比较了5-FU和776 C85片剂单药与每种规格的775 C85和5-FU片剂复方制剂。将每例受试者随机分配至6个治疗序列之一，并在每个研究阶段接受3种治疗之一，在研究期间接受所有3种治疗。每个阶段包括2天给药和5天洗脱期。776 C85（20 mg）在每个阶段的第1天每日两次单药给药，第2天晚上单次给药。所有患者在第2天早晨接受2.0 mg剂量的5-FU和20 mg剂量的776 C85。在每次5-FU给药后采集系列血样，以测量血浆5-FU、776 C85和尿嘧啶浓度。结果：本研究于1998年4月20日结束招募。这项研究达到了其应计目标。共入组11例杜克患者。所有患者都完成了这项I期研究，并在一项单独的开放标签研究中继续接受药物治疗。无需报告的不良事件。总体而言，患者的生活质量似乎有所改善，症状减轻，疾病稳定。未来计划：根据本试验的结果，复方片剂将用于进一步研究。

Purpose: This phase I study was designed to determine the bioequivalence of a tablet combining the chemotherapeutic agent 776C85/5-FU to the individual 776C85 and 5-FU tablets. Advantages of a combination tablet include a reduction in the chance that a patient would receive 776C85 and a standard dose of FU, which could result in a fatal toxicity. It makes it easier for patients to take the medication, and it ensures that patients do not take oral 5-FU without 776C85. In preclinical and early clinical studies, 776C85 significantly increased the bioavailability and half-life of oral 5-FU, and reduced the pharmacokinetic variability of oral 5-FU. It also increased the antitumor efficacy of 5-FU and increased the therapeutic index of 5-FU up to six-fold in rodent tumor models. Methods: This was a randomized, open-label 3-way crossover study in 36 patients comparing individual 5-FU and 776C85 tablets to each strength of the combination of 775C85 and 5-FU tablet. Each subject was randomly assigned to one of six treatment sequences and received one of three treatments during each study period and all three treatments during the study. Each period consisted of two days of dosing and a five-day washout. 776C85 (20 mg) was administered as a single agent twice daily on day 1 and as a single evening dose on day 2 of each period. All patients received a 2.0 mg dose of 5-FU and a 20 mg dose of 776C85 on the morning of day 2. Serial blood samples were collected following each dose of 5-FU to measure plasma 5-FU, 776C85, and uracil concentrations. Results: This study was closed to accrual on 4/20/98. The study met its accrual goal. A total of 11 Duke patients were enrolled. All of the patients completed this phase I study and continued to receive drug under a separate open-label study. There were no reportable adverse events. Overall, patients appeared to have improvement in their quality of life with decreased symptoms and stabilization of disease. Future plans: Based on the results of this trial, the combination tablet will be used in further studies.