Phase I study of paclitaxel by three-hour infusion: Hypotension just after infusion is one of the major dose-limiting toxicities
Phase I study of paclitaxel by three-hour infusion: Hypotension just after infusion is one of the major dose-limiting toxicities
复制标题
DOI：
10.1111/j.1349-7006.1995.tb03316.x
复制
发表时间：
1995-12-01
期刊：
影响因子：
--
通讯作者：
Saijo, N
中科院分区：
文献类型：
--
作者：
Tamura, T;Sasaki, Y;Saijo, N
本研究的主要目的是确定实体瘤患者3小时输注紫杉醇的最大耐受剂量（MTD），并比较3小时输注与24小时输注的药代动力学特征。27名患者分别接受了紫杉醇105、135、180、210、240和270 mg/m2六种剂量水平中的一种，并进行术前用药。2例接受240 mg/m2的患者和1例接受270 mg/m2的患者在完成紫杉醇输注后意外发生3/4级低血压。在270 mg/m2时，周围神经病变也是剂量限制性的（2）。虽然粒细胞减少症的严重程度明显低于24小时输注，但超过一半的患者在240或270 mg/m2的剂量下出现4级毒性（2）。未观察到重度超敏反应（HSR）。使用高效液相色谱法的药代动力学研究表明，随着剂量的增加，血浆峰浓度和曲线下面积成比例地增加，清除率和分布容积降低，表明紫杉醇3小时输注给药时的非线性药代动力学。紫杉醇输注3小时的MTD确定为240 mg/m2，并伴有粒细胞减少、周围神经病变和低血压的剂量限制性毒性。紫杉醇输注3小时后立即出现低血压是一种新的观察结果，此前尚未报道。II期研究的推荐剂量为210 mg/m（2）。尽管低血压是一种非预期的毒性作用，但紫杉醇在术前用药和适当监测下可安全给药3小时以上，与24小时输注相比，骨髓毒性降低，HSR发生率未增加。
The primary objectives of this study were to determine the maximum tolerated dose (MTD) of paclitaxel administered by 3-h infusion to patients with solid tumors, and to characterize the pharmacokinetics of a 3-h infusion in comparison with those of a 24-h infusion. Twenty-seven patients each received one of six levels of paclitaxel, 105, 135, 180, 210, 240 and 270 mg/m(2), with premedication. Two patients given 240 mg/m(2) and one patient given 270 mg/m(2) unexpectedly had grade 3/4 hypotension just after finishing the paclitaxel infusion. Peripheral neuropathy was also dose-limiting at 270 mg/m(2). Although granulocytopenia was significantly less severe than with a 24-h infusion, more than half of the patients experienced grade 4 toxicity at doses of 240 or 270 mg/m(2). Severe hypersensitivity reactions (HSRs) were not observed. Pharmacokinetic studies using high performance liquid chromatography demonstrated proportionally greater increases in the peak plasma concentration and area under the curve, and decreases in clearance and volume of distribution with increasing dose, suggesting non-linear pharmacokinetics of paclitaxel when given by 3-h infusion. The MTD of paclitaxel given as a 3-h infusion was determined to be 240 mg/m(2) with dose-limiting toxicities of granulocytopenia, peripheral neuropathy and hypotension. Hypotension just after infusion, induced by 3-h infusion of paclitaxel, is a new observation which has not been reported previously. The recommended dose for phase II study is 210 mg/m(2). Although hypotension was observed as an unexpected toxic effect, paclitaxel could be administered safely over 3 h with premedication and proper monitoring, resulting in reduced myelotoxicity and with no increase in the incidence of HSRs as compared with a 24-h infusion.