Phase I and Pharmacokinetic Study of Flavone Acetic Acid1

Flavone acetic acid is the second in a series of compounds based on the flavonoid aglycone ring structure to be clinically evaluated in malig nant disease. Preclinical studies have indicated that a minimum plasma level of ISO MH/mlis required before therapeutic efficacy (in a wide range of experi mental tumors) is seen in mice; both in vitro and in vivo studies also suggest that the duration of drug exposure is crucial in determining activity. Thus a Phase I trial has been performed in a total of 54 patients using 3 schedules, i.e., al-, 3-, and 6-h infusion. In each case, treatment was given once weekly for a minimum of 3 weeks. The maximum tolerated doses were 6.4, 6.4, and 10.0 g/m2, respectively. Dose limiting toxicity was denoted by an intense feeling of warmth and flushing with a 1-h infusion, hypotension with a 3-h infusion, and hypotension and diarrhea with a 6-h infusion. No objective responses were seen in this Phase I trial. The recommended doses for Phase II trials of flavone acetic acid in Europe are 4.K g/m2 over l h or 8.6 g/m2 over 6 h. At these doses the peak plasma concentrations obtained are 650 and 388 fig/ml, respectively. Total drug exposure (assessed by an area under the curve > 100 MR/HI!) was approximately 50% greater for the 6-h schedule. This Phase I trial indicates that peak plasma concentrations associated with experimental activity are achievable in humans, although optimal drug exposure times have not yet been defined.