title: Alteration of dacarbazine pharmacokinetics after interleukin-2 administration in melanoma patients.
abstract: 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.
authors: Division of Hematology and Oncology, Wayne State University School of Medicine, Detroit, Michigan 48201-1998.
authors: G G
authors: GG
authors: Chabot
authors: L E
authors: LE
authors: Flaherty
authors: M
authors: M
authors: Valdivieso
authors: L H
authors: LH
authors: Baker
mesh_terms: D002851:Chromatography, High Pressure Liquid; D003606:Dacarbazine / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004347:Drug Interactions; D006801:Humans; D007275:Injections, Intravenous; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D008545:Melanoma / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary
chemical_list: D007376:Interleukin-2; D003606:Dacarbazine