Cancer ChemotherPharmacol (1990) 27: 157-160 ancer hemotherapyand harmacology 9 Springer-Verlag1990 Alteration of dacarbazine pharmacokinetics after interleukin-2 administration in melanoma patients* Guy G. Chabot, Lawrence E. Flaherty, Manuel Valdivieso, and Laurence H. Baker Division of Hematology and Oncology,WayneState UniversitySchoolof Medicine,P. O. Box 02188, Detroit,Michigan 48201-1998, USA Received23 October i989/Accepted18 May 1990 Summary. In an effort to improve the treatment of meta- static malignant melanoma, we evaluated the sequential administration of the chemotherapeutic agent dacarbazine (DTIC) and the biological response modifier interleukin-2 (rlL-2) in a phase I-II study. Since the combination of biological response modifiers and chemotherapeutic agents could alter drug disposition, we evaluated the phar- macokinetics of DTIC and its major metabolite, 5-amino- imidazole 4-carboxamide (AIC), before and after rIL-2 administration. DTIC (1 g/m 2, 24-h i.v. infusion) was giv- en on day 1 and rlL-2 (2-4 million Cetus units/m 2, 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 administra- tion 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 (C1T) 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 rlL-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 c~-and [3-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 c~- and [3-half-lives of 0.7 and 11.4 h, respectively. Urinary excretion of DTIC and AIC * This study was supportedby a contractfrom Cetus Corporation(Eme- ryville, California)and by WayneState UniversityBen Kasle Trust Fund for Cancer Research Off)orint requests to: Dr. Guy G. Chabot, InstitutGustave-Roussy, Pavil- Ion de Recherche,39 rue Camille Desmoulins, F-94805 VillejuifCedex, France 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 administra- tion 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 regi- mens that include high-dose rIL-2. Introduction In an effort to improve the treatment of metastatic malig- nant 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 [4]. The choice of these agents is based on their demonstrated activity in metastatic malignant mela- noma and their non-overlapping toxicities. DTIC is consid- ered to be the standard single chemotherapeutic agent in metastatic malignant melanoma when treatment is indi- cated [8], and rIL-2 was recently reported to be active in metastatic malignant melanoma [9]. Since the combination of biological response modifiers and chemotherapeutic agents can alter the pharmacokinet- ics of the latter [1, 3, 6, 7, 10], we evaluated the pharma- cokinetics of DTIC and its major metabolite, 5-amino-im- idazole 4-carboxamide (AIC), before and after rIL-2 ad- ministration. We report that the plasma pharmacokinetics of DTIC is significantly altered after rIL-2 administration. Patients and methods Patients. Patients with histologicallyconfirmed, measurable and unre- sectable metastatic malignant melanoma were eligible for this study.