PHASE-I EVALUATION OF ALL-TRANS-RETINOIC ACID WITH AND WITHOUT KETOCONAZOLE IN ADULTS WITH SOLID TUMORS

Purpose: All-trans retinoic acid (RA) induces accelerated plasma oil-t rans RA clearance, presumably via cytochrome P450 enzymes. This accele rated metabolism has been shown to be inhibited in the short term by t he cytochrome P450 inhibitor ketoconazole. This study was conducted to evaluate the efficacy of ketoconazole in maintaining plasma all-trans RA levels over time. Patients and Methods: Using a randomized crossov er study design, we randomly assigned six patients to receive all-tran s RA (45 mg/m(2) orally twice per day for 14 days of a 21-day cycle) f or cycle 1 and the same dose of all-trans RA plus ketoconazole (400 mg orally for one dose, then 200 mg orally three times per day for 14 da ys) for cycle 2, and seven patients to receive the some treatment in t he reverse order, plasma all-trans RA levels were measured during the initial 8-hour period after all-trans RA ingestion on days 1 and 15 of cycles 1 and 2, Results: There was a marked decrease in plasma all-tr ans RA levels after 14 days of treatment, as measured by the area unde r the concentration-time curve (AUG), regardless of whether ketoconazo le wets given (from ct baseline value of 857 to 44 ng/mL/h; P = .025) or not (from 1,355 to 308 ng/ml/h; P = .123). This lack of effect on p lasma all-trans RA levels was not due to inadequate plasma ketoconazol e levels. Ketoconazole administration was associated with more toxicit y. No objective tumor responses were observed. Conclusion: Ketoconazol e does not appear to maintain adequate plasma all-trans RA levels over time. (C) 1995 by American Society of Clinical Oncology.