PHARMACOKINETICS OF TEMOZOLOMIDE IN ASSOCIATION WITH FOTEMUSTINE IN MALIGNANT-MELANOMA AND MALIGNANT GLIOMA PATIENTS - COMPARISON OF ORAL, INTRAVENOUS, AND HEPATIC INTRAARTERIAL ADMINISTRATION

Purpose: Depletion of the DNA repair enzyme O-6-alkylguanine-DNA alkyl transferase (AT) has been shown to increase tumor sensitivity to chlor oethyl-nitrosoureas. Temozolomide (TMZ), an analogue of dacarbazine, c an deplete AT, suggesting that it may be used to sensitize tumors to c hloroethylnitrosoureas. However, the influence of nitrosoureas on the pharmacokinetics of TMZ is unknown, and a pilot study was performed to assess the pharmacokinetics of TMZ given via, various routes to 29 pa tients (27 malignant melanomas, 2 gliomas) with or without sequential administration of i.v. fotemustine. Methods: On day 1, TMZ was given i ntravenously (i.v.), orally (p.o.), or by intrahepatic arterial infusi on (h.i.a.) at four ascending dose levels (150 to 350 mg/m(2) per day) . On day 2 the same dose of TMZ was given by the same route (or by ano ther route in six patients for determination of its bioavailability), followed 4 h later by fotemustine infusion at 100 mg/m(2) Plasma and u rinary levels of TMZ were determined on days 1 and 2 by high-performan ce liquid chromatography after solid-phase extraction. Results: The ph armacokinetics of i.v. TMZ appeared linear, with the area under the cu rve (AUC) increasing in proportion to the dose expressed in milligrams per square meter (r = 0.86 and 0.91 for days 1 and 2, respectively). The clearance after i.v. administration was 220 +/- 48 and 241 +/- 39 ml/min on days 1 and 2, respectively. The apparent clearance after p.o . and h.i.a. administration was 290 +/- 86 and 344 +/- 77 ml/min, resp ectively. The volume of distribution of TMZ after i.v., p.o., and h.i. a. administration was 0.4, 0.6, and 0.6 l/kg on day 1 and 0.5, 0.5, an d 0.6 l/kg on day 2, respectively. The absolute bioavailability of TMZ was 0.96 +/- 0.1, regardless of the sequence of the i.v.-p.o. or p.o. -i.v. administration, confirming that TA IZ is not subject to a marked first-pass effect. A comparison of TMZ pharmacokinetics after i.v. an d h.i.a. treatment at the same infusion rate revealed little evidence of hepatic extraction of TMZ. However, the systemic exposure to TMZ (A UC) appeared to decrease at a lower infusion rate. TMZ excreted unchan ged in the urine accounted for 5.9 +/- 3.4% of the dose, with low with in-patient and high interpatient variability. TMZ crosses the blood-br ain barrier and the concentration detected in CSF amounted to 9%, 28%, and 29% of the corresponding plasma levels (three patients). The equi librium between plasma and ascitic fluid was reached after 2 h (assess ed in one patient). Conclusion: The sequential administration of fotem ustine at 4 h after TMZ treatment had no clinically relevant influence on the pharmacokinetics of TMZ. The potential clinical effect of TMZ given by h.i.a. or by locoregional administration has yet to be establ ished, as has the impact of the infusion duration on patients' toleran ce and response rate.