PHASE-I STUDY OF AMONAFIDE DOSING BASED ON ACETYLATOR PHENOTYPE

Amonafide is extensively metabolized, including N-acetylation to an ac tive metabolite. Prior studies have demonstrated that patients who are fast acetylators of amonafide (and other drugs) have increased toxici ty at standard doses of amonafide. The primary objective of this study was to define the recommended phase II dose of amonafide separately f or slow and fast acetylators. Twenty-six patients with advanced cancer underwent acetylator phenotyping with caffeine and were assigned to a dose level. Slow acetylators were treated at 375 mg/m2 (daily for 5 d ays) and had a median WBC nadir of 1600/mul. Fast acetylators were tre ated at both 200 and 250 mg/m2, resulting in median WBC nadirs of 5300 and 2000/mul, respectively. Two patients were not typeable, and two p atients appear to have been misphenotyped, one in each phenotype categ ory. Pharmacodynamic analysis yielded a model for nadir WBC including acetylator phenotype, 24-h N-acetyl-amonafide plasma concentration, ge nder, and pretreatment WBC. We recommend doses of 250 and 375 mg/m2 (f or 5 days) for further phase II testing of amonafide in fast and slow acetylators, respectively.