Korfel A, Scheulen M E, Schmoll H J, Gründel O, Harstrick A, Knoche M, Fels L M, Skorzec M, Bach F, Baumgart J, Sass G, Seeber S, Thiel E, Berdel W E
Benjamin Franklin Hospital, Free University of Berlin, Germany.
Clin Cancer Res. 1998 Nov;4(11):2701-8.
This Phase I dose-escalation clinical trial of a lyophilized formulation of titanocene dichloride (MKT4) was conducted to determine the maximum tolerated dose, the dose-limiting toxicity (DLT), and pharmacokinetics of titanium (Ti) after a single i.v. infusion of MKT4. Forty patients with refractory solid malignancies were treated with a total of 78 courses. Using a modified Fibonacci scheme, 15 mg/m2 initial doses of titanocene dichloride were increased in cohorts of three patients up to level 11 (560 mg/m2) if DLT was not observed. The maximum tolerated dose was 315 mg/m2, and nephrotoxicity was DLT. Two minor responses (bladder carcinoma and non-small cell lung cancer) were observed. The pharmacokinetics of plasma Ti were assessed in 14 treatment courses by atomic absorption spectroscopy. The ratio for the area under the curve(0-infinity) in plasma and whole blood was 1.2. The following pharmacokinetic parameters were determined for plasma, as calculated in a two-compartment model: biological half-life t1/2beta in plasma was 22.8+/-11.2 h (xh +/- pseudo-SD), peak plasma concentration cmax approximately 30 microg/ml at a dose of 420 mg/m2, distribution volume Vss= 5.34+/-2.1 L (xa +/- SD), and a total clearance CItotal = 2.58+/-1.23 ml/min (xa +/- SD). There was a linear correlation between the area under the curve(0-infinity) of Ti in plasma and the titanocene dichloride dose administered with a correlation coefficient r2 of 0.8856. Plasma protein binding of Ti was in the 70-80% range. Between 3% and 16% of the total amount of Ti administered were renally excreted during the first 36 h. The recommended dose for Phase II evaluation is 240 mg/m2 given every 3 weeks with i.v. hydration to reduce renal toxicity.
本项关于二氯二茂钛冻干制剂（MKT4）的I期剂量递增临床试验旨在确定最大耐受剂量、剂量限制性毒性（DLT）以及单次静脉输注MKT4后钛（Ti）的药代动力学。40例难治性实体恶性肿瘤患者共接受了78个疗程的治疗。采用改良斐波那契方案，若未观察到DLT，则在每组3例患者中，将二氯二茂钛的初始剂量15mg/m²逐步增加至11级（560mg/m²）。最大耐受剂量为315mg/m²，肾毒性为DLT。观察到2例轻微缓解（膀胱癌和非小细胞肺癌）。通过原子吸收光谱法在14个治疗疗程中评估了血浆Ti的药代动力学。血浆和全血中曲线下面积（0至无穷大）的比值为1.2。根据二室模型计算得出血浆的以下药代动力学参数：血浆中的生物半衰期t1/2β为22.8±11.2小时（xh±伪标准差），在剂量为420mg/m²时血浆峰值浓度cmax约为30μg/ml，分布容积Vss = 5.34±2.1L（xa±标准差），总清除率CItotal = 2.58±1.23ml/min（xa±标准差）。血浆中Ti的曲线下面积（0至无穷大）与所给予的二氯二茂钛剂量之间存在线性相关性，相关系数r2为0.8856。Ti的血浆蛋白结合率在70%至80%范围内。在给药后最初36小时内，3%至16%的总给药量经肾脏排泄。II期评估的推荐剂量为每3周静脉输注240mg/m²，并进行静脉补液以降低肾毒性。
