Phase I trial of marimastat, a novel matrix metalloproteinase inhibitor, administered orally to patients with advanced lung cancer
Phase I trial of marimastat, a novel matrix metalloproteinase inhibitor, administered orally to patients with advanced lung cancer
复制标题
DOI：
10.1200/jco.1998.16.6.2150
复制
发表时间：
1998-06-01
影响因子：
45.3
通讯作者：
Hawkins, MJ
中科院分区：
文献类型：
--
作者：
Wojtowicz-Praga, S;Torri, J;Hawkins, MJ
目的：进行这一I期研究，以评估安全性和药物动力学的剂量递增的Marimastat（英国Biatech公司，牛津，英国）在晚期恶性肿瘤患者，并确定II期推荐剂量用于后续study.Patients和方法：一个标准的I期设计中使用的研究中，连续三组患者进行治疗与剂量递增的研究药物。Marimastat以25、50或100 mg每日两次口服给药于连续组的晚期肺癌患者。在研究的最高剂量（100 mg口服，每日两次）下增加了另外3例患者，以评估在以下剂量下观察到的炎性多关节炎是否发生。该剂量水平可通过同时给予非甾体类抗炎药（NSAIDS）和/或低剂量皮质类固醇来预防。抽取血液用于安全性监测、药代动力学分析和金属蛋白酶（MMP）-2和MMP-9的血浆水平（通过酶谱法测定）。总共有12名患者进行了研究。结果：在最高剂量的研究（100毫克口服每日两次）最显着的毒性是一个症状性的炎性多关节炎，持续长达8周后，停止研究药物和剂量限制。Marimastat的估计血浆消除半衰期为4 - 5小时，合理耐受剂量（50 mg口服，每日两次）下的平均最大浓度（C-max）为196 ng/mL，在给药后1 - 2小时（T-max）内达到。曲线下面积（AUC）倾向于与Marimastat的剂量相关。酶谱分析活化的MMP-2和-9的促酶形式的外周血比率没有显示出任何一致的模式的变化，MMP水平或在一定程度上的活化过程中的治疗course.Conclusion：Marimastat是从胃肠道吸收良好，与高水平的研究药物在血浆中检测后几个小时内给药。剂量水平2和3（50 mg和100 mg，每日两次口服）达到的Marimastat血浆浓度显著高于体外MMP抑制所需的浓度。剂量限制性毒性（DLT）为严重的炎性多关节炎，这似乎是一种累积毒性。(C)1998年，美国临床肿瘤学会。
Purpose: This phase I study was performed to evaluate the safety and pharmacokinetics of escalating doses of Marimastat (British Biatech, Inc, Oxford, United Kingdom) in patients with advanced malignancies and to determine the phase II recommended dose to be used in subsequent studies.Patients and Methods: A standard phase I design was used in this study in which consecutive groups of three patients were treated with escalating doses of the study drug. Marimastat was administered orally at 25, 50, or 100 mg twice daily to consecutive groups of patients with advanced lung cancer. An additional three patients were added at the highest dose studied (100 mg orally twice daily) to assess whether the inflammatory polyarthitis observed at. that dose level can be prevented by a concurrent administration of nonsteroidal antiinflammatory drugs (NSAIDS) and/or low-dose corticosteroids. Blood was drawn for safety monitoring, pharmacokinetic analysis, and plasma levels of metalloproteinase (MMP)-2 and MMP-9 (determined by zymography). A total of 12 patients were studied.Results: The most significant toxicity at the highest dose studied (100 mg orally twice daily) was a symptomatic inflammatory polyarthritis that persisted for up to 8 weeks after discontinuation of the study drug and was dose-limiting. The estimated plasma elimination half-life of Marimastat was 4 to 5 hours, The mean maximum concentration (C-max) at a reasonably well-tolerated dose (50 mg orally twice daily) was 196 ng/mL and was reached within 1 to 2 hours (T-max) after administration. Areas under the curve (AUC) tended to correlate with the dose of Marimastat. Zymographic analysis of peripheral-blood ratios of activated proenzymatic forms of MMP-2 and -9 did not show any consistent patterns of change in MMP levels or in a degree of their activation during the course of treatment.Conclusion: Marimastat was well absorbed from the gastrointestinal tract, with high levels of the study drug detected in plasma within hours after drug administration. Plasma concentrations of Marimastat achieved at dose levels 2 and 3 (50 mg and 100 mg orally twice daily) were substantially higher than those required for MMP inhibition in vitro. The dose limiting toxicity (DLT) was severe inflammatory polyarthritis, which seemed to be a cumulative toxicity. (C) 1998 by American Society of Clinical Oncology.