Weiss G R, Poggesi I, Rocchetti M, DeMaria D, Mooneyham T, Reilly D, Vitek L V, Whaley F, Patricia E, Von Hoff D D, O'Dwyer P
Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, USA.
Clin Cancer Res. 1998 Jan;4(1):53-9.
Tallimustine [PNU 152241 (FCE 24517)] is a synthetic derivative of the DNA minor groove binder distamycin A, in which the NH2-terminal formyl group is substituted by benzoyl mustard. In this Phase I clinical trial, patients with advanced solid tumors received i.v. bolus injections of tallimustine daily for 3 consecutive days. Patients were treated at six dosage levels of 33.3 micrograms/m2/day to 250 micrograms/m2/day for 3 consecutive days, with courses of therapy repeated every 28 days. Detailed pharmacokinetic blood sampling was performed during the first 3 days of the first course of tallimustine. The plasma samples were analyzed by high-performance liquid chromatography with UV detection. Forty-eight eligible patients were treated at all six dosage levels. The dominant dose-related toxicity of tallimustine was neutropenia, becoming dose limiting at 250 micrograms/m2/day. At this dosage level, one patient experienced febrile neutropenia, and a second patient died on study of indeterminate cause. Thrombocytopenia was not observed, and only 10 patients developed anemia < 8.0 gm/dl. Sporadic elevation of liver enzymes or bilirubin was observed but was not dose related. Pharmacokinetic analysis gave reliable results for 33 patients. For most patients, analysis of the data best fit a three-exponential model. Dose-related increases in areas under the concentration-time curve and end-of-infusion concentrations were observed. There was no significant plasma accumulation of tallimustine over the 3 days of administration. The terminal half-life of tallimustine in individual patients ranged from 6.83 to 39.02 h following the last dose. In summary, the recommended Phase II dosage for tallimustine is 200 micrograms/m2/day for 3 consecutive days every 28 days. Neutropenia is the principal toxicity of this agent at this dosage and schedule.
他利莫司汀[PNU 152241 (FCE 24517)]是DNA小沟结合剂偏端霉素A的合成衍生物，其中NH2末端的甲酰基被苯甲酰氮芥取代。在这项I期临床试验中，晚期实体瘤患者接受静脉推注他利莫司汀，连续3天每日给药。患者按33.3微克/平方米/天至250微克/平方米/天的六个剂量水平连续3天给药，每28天重复一个疗程。在他利莫司汀第一个疗程的前3天进行详细的药代动力学血样采集。血浆样本通过带紫外检测的高效液相色谱法进行分析。48名符合条件的患者在所有六个剂量水平接受了治疗。他利莫司汀主要的剂量相关毒性是中性粒细胞减少，在250微克/平方米/天剂量时成为剂量限制毒性。在此剂量水平，一名患者发生发热性中性粒细胞减少，第二名患者在研究过程中因不明原因死亡。未观察到血小板减少，只有10名患者出现血红蛋白<8.0克/分升的贫血。观察到肝酶或胆红素偶尔升高，但与剂量无关。33名患者的药代动力学分析得出可靠结果。对于大多数患者，数据分析最符合三指数模型。观察到浓度-时间曲线下面积和输注结束时浓度与剂量相关增加。在给药的3天内他利莫司汀没有明显的血浆蓄积。最后一剂后，他利莫司汀在个体患者中的终末半衰期为6.83至39.02小时。总之，他利莫司汀推荐的II期剂量是每28天连续3天每日200微克/平方米。在此剂量和给药方案下，中性粒细胞减少是该药物的主要毒性。
