晚期癌症患者中输注氟尿嘧啶联合重组干扰素α-2b的Ⅰ期及血浆药代动力学研究

Phase I and plasma pharmacokinetic study of infusional fluorouracil combined with recombinant interferon alfa-2b in patients with advanced cancer.

作者信息

Danhauser L L, Freimann J H, Gilchrist T L, Gutterman J U, Hunter C Y, Yeomans A C, Markowitz A B

机构信息

Department of Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030.

出版信息

J Clin Oncol. 1993 Apr;11(4):751-61. doi: 10.1200/JCO.1993.11.4.751.

DOI:10.1200/JCO.1993.11.4.751

PMID:8478667

Abstract

PURPOSE

Enhanced fluorouracil (FUra) cytotoxicity caused by recombinant interferon alfa-2b (rIFN-a) has been reported, but the mechanism, optimal dose, and schedule remain unknown. Therefore, a phase I and pharmacokinetic study of FUra with escalating doses of rIFN-a was initiated.

PATIENTS AND METHODS

FUra (750 mg/m2/d) was given by continuous intravenous (IV) infusion for 5 days. rIFN-a (0.1 to 15 x 10(6) U/m2/d) was given subcutaneously (SC) daily for 5 days concurrent with FUra. Courses were repeated every 14 to 21 days. Forty-four patients were enrolled; 39 received at least two courses. During the first course of therapy, FUra levels before and after administration of rIFN-a were quantitated in 26 patients by high-pressure liquid chromatography.

RESULTS

The maximum-tolerated dose of rIFN-a was 10 x 10(6) U/m2/d. Stomatitis was dose-limiting. Three partial and five minor responses occurred. Interpatient pharmacokinetics showed that rIFN-a did not alter steady-state plasma concentration (Css; range, 0.77 +/- 0.35 mumol/L to 1.85 +/- 0.48 mumol/L), elimination half-life (t1/2; mean, 9.7 +/- 4.3 minutes), area under the concentration-versus-time curve (AUC; range, 93 to 224 mumol/L x hours), total-body clearance (CI; range, 1,172 to 3,236 mL/min), or volume of distribution (range, 11.9 to 49.2 L) of FUra. Intrapatient data evaluation revealed a dose-independent effect of rIFN-a. The mean FUra Css after rIFN-a administration (1.31 mumol/L) was greater than that before rIFN-a administration (1.02 mumol/L, P < .0001). FUra Cl after rIFN-a administration was reduced by 20% to 35% compared with use of FUra alone (P < .0001). Patients with a greater than 20% decrease in FUra Cl had a fourfold greater incidence of diarrhea.

CONCLUSION

rIFN-a reduces FUra Cl and, consequently, increases FUra-associated toxicity. Phase II studies of FUra and rIFN-a seem to be warranted.

摘要

目的

已有报道称重组干扰素α-2b（rIFN-α）可增强氟尿嘧啶（FUra）的细胞毒性，但具体机制、最佳剂量和给药方案仍不清楚。因此，开展了一项FUra联合递增剂量rIFN-α的Ⅰ期及药代动力学研究。

患者与方法

FUra（750mg/m²/d）持续静脉输注5天。rIFN-α（0.1至15×10⁶U/m²/d）在给予FUra的同时皮下注射，每日1次，共5天。每14至21天重复一个疗程。共纳入44例患者，39例接受了至少两个疗程的治疗。在第一个疗程治疗期间，通过高压液相色谱法对26例患者在给予rIFN-α前后的FUra水平进行了定量分析。

结果

rIFN-α的最大耐受剂量为10×10⁶U/m²/d。口腔炎是剂量限制性毒性。出现了3例部分缓解和5例轻度缓解。患者间药代动力学显示，rIFN-α未改变FUra的稳态血药浓度（Css；范围为0.77±0.35μmol/L至1.85±0.48μmol/L）、消除半衰期（t1/2；平均为9.7±4.3分钟）、浓度-时间曲线下面积（AUC；范围为93至224μmol/L·小时）、全身清除率（CI；范围为1172至3236mL/min）或分布容积（范围为11.9至49.2L）。患者内数据评估显示rIFN-α具有剂量非依赖性效应。给予rIFN-α后FUra的平均Css（1.31μmol/L）高于给予rIFN-α前（1.02μmol/L，P<0.0001）。与单独使用FUra相比，给予rIFN-α后FUra的CI降低了20%至35%（P<0.0001）。FUra的CI降低超过20%的患者腹泻发生率高出4倍。