Chabot G G, Flaherty L E, Valdivieso M, Baker L H
Division of Hematology and Oncology, Wayne State University School of Medicine, Detroit, Michigan 48201-1998.
Cancer Chemother Pharmacol. 1990;27(2):157-60. doi: 10.1007/BF00689102.
In an effort to improve the treatment of metastatic malignant melanoma, we evaluated the sequential administration of the chemotherapeutic agent dacarbazine (DTIC) and the biological response modifier interleukin-2 (rIL-2) in a phase I-II study. Since the combination of biological response modifiers and chemotherapeutic agents could alter drug disposition, we evaluated the pharmacokinetics of DTIC and its major metabolite, 5-amino-imidazole 4-carboxamide (AIC), before and after rIL-2 administration. DTIC (1 g/m2, 24-h i.v. infusion) was given on day 1 and rIL-2 (2-4 million Cetus units/m2, 30-min i.v. injection), on days 15-19 and 22-26 of each course of therapy. The second DTIC dose was given on day 29, i.e., 3 days after the last rIL-2 administration. DTIC and AIC were assayed by reversed-phase HPLC. DTIC plasma levels showed a significant decrease after rIL-2 administration as compared with DTIC values obtained in the same patients before rIL-2 administration. DTIC area under the curve (AUC) values obtained after rIL-2 were lower than those obtained on day 1 before rIL-2 administration (P = 0.02). After rIL-2, the total body clearance (ClT) was increased (P = 0.04), as was the volume of distribution at steady state (Vss; P = 0.02). The decrease in AUC after rIL-2 administration became more pronounced as the rIL-2 dose was increased (P = 0.03). No significant difference was detected in the elimination phase of DTIC when half-lives obtained before and after rIL-2 administration were compared; the mean half-lives were 0.7 and 2.8 h for the alpha- and beta-phases, respectively. The model-independent mean residence time was 3.4 h. The plasma AUC for the metabolite AIC did not charge after rIL-2 administration. AIC biphasic plasma elimination was also similar after rIL-2 administration, with alpha- and beta-half-lives of 0.7 and 11.4 h, respectively. Urinary excretion of DTIC and AIC did not differ after rIL-2 administration; the overall DTIC excretion was 39% of the dose over 48 h, and AIC urinary excretion was 25% of the DTIC dose. The observed decrease in the DTIC plasma AUC after rIL-2 administration appears to be due to an increase in the volume of distribution, since other factors such as half-lives, urinary excretion, and metabolism were not significantly altered. The clinical consequences of the rIL-2-DTIC interaction remain difficult to assess based on presently available data, but this drug interaction should be taken into consideration in the development of future chemo-immunotherapy regimens that include high-dose rIL-2.
为了改善转移性恶性黑色素瘤的治疗效果，我们在一项I-II期研究中评估了化疗药物达卡巴嗪（DTIC）和生物反应调节剂白细胞介素-2（rIL-2）的序贯给药。由于生物反应调节剂与化疗药物联合使用可能会改变药物的处置，我们在给予rIL-2前后评估了DTIC及其主要代谢产物5-氨基-咪唑4-甲酰胺（AIC）的药代动力学。DTIC（1 g/m²，静脉滴注24小时）于第1天给药，rIL-2（200 - 400万Cetus单位/m²，静脉注射30分钟）于每个疗程的第15 - 19天和22 - 26天给药。第二次DTIC剂量于第29天给药，即最后一次给予rIL-2后3天。DTIC和AIC通过反相高效液相色谱法进行测定。与rIL-2给药前同一患者的DTIC值相比，rIL-2给药后DTIC血浆水平显著降低。rIL-2给药后获得的DTIC曲线下面积（AUC）值低于rIL-2给药前第1天获得的值（P = 0.02）。给予rIL-2后，总体清除率（ClT）增加（P = 0.04），稳态分布容积（Vss）也增加（P = 0.02）。随着rIL-2剂量增加，rIL-2给药后AUC的降低变得更加明显（P = 0.03）。比较rIL-2给药前后获得的半衰期时，未检测到DTIC消除相有显著差异；α相和β相平均半衰期分别为0.7小时和2.8小时。非模型依赖的平均驻留时间为3.4小时。rIL-2给药后代谢产物AIC的血浆AUC没有变化。rIL-2给药后AIC的双相血浆消除也相似，α相和β相半衰期分别为0.7小时和11.4小时。rIL-2给药后DTIC和AIC的尿排泄没有差异；48小时内DTIC的总体排泄量为剂量（给药量）的39%，AIC的尿排泄量为DTIC剂量的25%。rIL-2给药后观察到的DTIC血浆AUC降低似乎是由于分布容积增加，因为半衰期、尿排泄和代谢等其他因素没有显著改变。基于目前可得的数据，rIL-2 - DTIC相互作用的临床后果仍然难以评估，但在未来包含高剂量rIL-2的化学免疫治疗方案的开发中应考虑这种药物相互作用。
