羟基喜树碱Ⅰ期药代动力学及人体耐受性临床研究

Phase Ⅰ Trial of Pharmacokinetics and Human Tolerability to 10-Hydroxycamptothecin in Patients with Advanced Malignancy

目的:研究羟基喜树碱(HCPT)在人体药代动力学,观察人体对其的耐受性。方法:分5个剂量级5.0mg/m2、7.5mg/m2、12mg/m2、16mg/m2、20mg/m2,按体表面积折算HCPT剂量并将其溶于0.9%NaCl液中,30min内恒速静脉滴入,连续用药5天,停药后观察2周。同时第一天于给药前、停药即刻、停药后15min、30min、1h、2h、4h、6h、8h、12h分别取2ml静脉血置肝素化试管中,用高效液相荧光法测定HCPT在人体的血药浓度,3p87计算药代动力学参数。结果:共有24例病人入选。剂量限制性毒性(DLT)为骨髓抑制和腹泻。随剂量增加,上述两种不良反应的发生率和强度呈线性增加。其它不良反应主要包括恶心、呕吐犤程度较轻(Ⅰ-Ⅱ度)、持续时间短(2-3天)犦、肝功能异常、血尿和皮疹。HCPT在体内呈二室模型,t1/2α0.0523-0.613h,t1/2β:1.03-2.42h,Vd:5.54-11.4L/m2。犤HCPT犦内酯占犤HCPT犦总的10%-20%,血浆蛋白结合率65%-99%,24h尿排泄率24%。结论:HCPT主要不良反应为骨髓抑制和消化道反应,随剂量增加,不良反应发生率、严重程度增加,停药或对症治疗能缓解。最大耐受剂量16mg·(m2·d)-1,临床推荐剂量12mg·(m2·d)-1。HCPT在体内主要以酸式结构存在,HCPT在体内呈二室模型。

Objective: The current study was designed to investigate pharmacokinetic profiles and to observe the human tolerance to 10 hydroxycamptothecin in the patients with advanced malignancy. Methods: HCPT is an topoisomerase Ⅰ inhibitor, obtained from Chinese tree Camptotheca acumineta. Its dose initiated at 5 mg/m2, was solved in 0.9%normal saline(NS) 100 ml and given as a 30 min infusion at constant speed for 5 consecutive days, then escalated to 7.5 mg/m2, 12 mg/m2, 16 mg/m2,and 20 mg/m2,respectively. The patients were evaluated for response and toxicity after two weeks. Heparinized blood samples(2 ml) were collected on the first infusion day, immediately predose (time 0), then postinfusion at 0, 15, 30 minutes, and 2, 4, 6, 8, 12 hours. Pharmacokinetics was evaluated by high performance liquid chromatography (HPLC). Results: Twenty four patients suitable for phase Ⅰ eligibility criteria were included (6 women,18 men; median age 52.61 years). The main toxicities were myelosuppression and diarrhea, and encounted at median and high doses level. Other toxcities involved Ⅰ-Ⅱ nausea/voimting, hepatic function disorder, hematuria,and exanthem. Pharmacokinetics was performed in 24 patients. HCPT plasma concentration was biphasic, with distribution half life and terminal elimination half life of 0.0523h-0.613h and 1.03h-2.42h respectively. Distribution volumes was 5.54-11.4L/m2. HCPT area under the plasma concentration versus time (AUC) and maximum concentration (Cmax) increased linearly with dose escalating. About 10-20% of the total HCPT circulating in plasma was in the lactone form. The rate of protein bound is 65%-99% Twenty four hour urinary excretion accounted for 24%of the dose. Conclusion: The dose limiting toxicities of HCPT in human were myelosuppression and diarrhea. morbidity and degree increased according with dose from 5 mg/m2 to 20 mg/m2. Toxicity was reversible and manageable. The maximum tolerance dosage (MTD) is 16 mg/m2, and the recommendation dose is 12 mg/m2. Carboxylate HCPT was the main form existing in plasma and HCPT plasma concentration was biphasic.