title: A phase I and pharmacokinetic study of 12-h infusion of flavone acetic acid.
abstract: This phase I study investigated flavone acetic acid (FAA) given as a 12-h intravenous infusion every 3 weeks in the absence of urinary alkalinisation. Cohorts of three patients were treated at doses of 7, 10 and 13 g/m2. One subject had colon cancer; 5, renal cancer; and 3, lung cancer. The Eastern Cooperative Oncology Group (ECOG) performance status was 0 in four patients, 1 in two subjects and 2 in three cases. The maximum tolerated dose was 13 g/m2. The dose-limiting toxicities were WHO grade 3 hypotension and grade 3 diarrhoea. Other toxicities included lethargy and dizziness, nausea, temperature fluctuation, myalgia and dry mouth, but no significant myelosuppression was encountered. One patient receiving 10 g/m2 for renal cancer showed a partial response that lasted for 3 months and included the resolution of pulmonary and cutaneous metastases. The pharmacokinetics showed large interpatient variability. At 12-16 h post-infusion, the plasma elimination profile entered a plateau phase, with frequent increases in concentration suggesting enterohepatic recycling. Neither peak FAA levels nor AUC values were dose-dependent at the doses studied. Peak plasma levels were 101-402 micrograms/ml and AUC (0-48 h) values were 75-470 mg ml-1 min. Plasma protein binding varied with total concentration. Two metabolites were detected in the plasma, and both also underwent apparent enterohepatic recycling. Repeat dosing resulted in decreases of up to 48% in peak levels and AUC values for FAA in three of six patients. Of the total FAA dose, 39%-77% was excreted in the urine as FAA or metabolites within 2 days. The dose recommended for further phase II studies is 10 g/m2.
authors.affiliation: Department of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia.
authors.forename: I N
authors.initials: IN
authors.lastname: Olver
authors.forename: L K
authors.initials: LK
authors.lastname: Webster
authors.forename: J F
authors.initials: JF
authors.lastname: Bishop
authors.forename: K H
authors.initials: KH
authors.lastname: Stokes
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000032:analysis / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D005419:Flavonoids / Q000008:administration & dosage / Q000009:adverse effects* / Q000032:analysis / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D012074:Remission Induction; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; C049328:flavone acetic acid