Phase I and pharmacokinetic study of flavone acetic acid.
Flavone acetic acid is the second in a series of compounds based on the flavonoid aglycone ring structure to be clinically evaluated in malignant disease. Preclinical studies have indicated that a minimum plasma level of 150 micrograms/ml is required before therapeutic efficacy (in a wide range of experimental 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., a 1-, 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 4.8 g/m2 over 1 h or 8.6 g/m2 over 6 h. At these doses the peak plasma concentrations obtained are 650 and 388 micrograms/ml, respectively. Total drug exposure (assessed by an area under the curve greater than 100 micrograms/ml) 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.
Kerr
D J
DJ
Department of Medical Oncology, University of Glasgow, Scotland.
Kaye
S B
SB
Cassidy
J
J
Bradley
C
C
Rankin
E M
EM
Adams
L
L
Setanoians
A
A
Young
T
T
Forrest
G
G
Soukop
M
M
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D005419:Flavonoids / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy
D000970:Antineoplastic Agents; D005419:Flavonoids; C049328:flavone acetic acid