Rodriguez G I, Kuhn J G, Weiss G, De La Cruz P, New P, Fields S M, Eckardt J R, Campbell L, Clark G M, Hilsenbeck S G, Von Hoff D D
The University of Texas Health Science Center at San Antonio, 78284-6220, USA.
Invest New Drugs. 1998;16(1):57-67. doi: 10.1023/a:1006003718255.
In this phase I study, terephthalamidine was administered as a 120-hour continuous infusion repeated every 21 days. Thirteen patients received 27 courses of terephthalamidine at four dose levels ( 14, 28, 46, and 70 mg/m2/day). Dose-limiting toxicity consisted of profound and intractable anorexia, weight loss and prostration in all patients. Toxicity was delayed and accompanied by hyponatremia and hypokalemia. No hematologic or other toxicity was documented. One patient with adenocarcinoma of the lung had a 40% decrease in mediastinal lymph nodes and resolution of a pleural effusion lasting 2 months. Pharmacokinetic analysis by HPLC was performed in all patients during their first course. The harmonic mean terminal half-life for terephthalamidine was 23 hours with a plasma clearance of 1.7 1/hr/m2. Both plasma concentrations achieved during infusion (r2 = 0.9) and area under the curve (AUC) (r2 = 0.8) were proportional to increase in dose (p < 0.002). Renal excretion accounted for 64% of the total cumulative dose, with an average renal clearance of 1.16 1/hr/m2. Due to the unacceptable toxicity seen at all doses with this schedule, no further studies are recommended unless the mechanism of toxicity is better understood and can be prevented.
在这项I期研究中，对苯二甲脒以120小时持续输注的方式给药，每21天重复一次。13名患者接受了四个剂量水平（14、28、46和70mg/m²/天）的27个疗程的对苯二甲脒治疗。剂量限制性毒性表现为所有患者均出现严重且难以控制的厌食、体重减轻和全身乏力。毒性出现延迟，并伴有低钠血症和低钾血症。未记录到血液学或其他毒性。一名肺癌腺癌患者的纵隔淋巴结缩小40%，胸腔积液消退持续2个月。在所有患者的第一个疗程中通过高效液相色谱法进行了药代动力学分析。对苯二甲脒的调和平均终末半衰期为23小时，血浆清除率为1.7l/小时/m²。输注期间达到的血浆浓度（r² = 0.9）和曲线下面积（AUC）（r² = 0.8）均与剂量增加成正比（p < 0.002）。肾排泄占总累积剂量的64%，平均肾清除率为1.16l/小时/m²。由于在此给药方案下所有剂量均出现不可接受的毒性，除非能更好地理解毒性机制并加以预防，否则不建议进一步研究。
