Phase I and pharmacokinetic study of brequinar sodium (NSC 368390).

摘要: Brequinar sodium is a quinoline carboxylic acid derivative that has shown antitumor activity in number of vivo murine and human tumor xenograft models. Its mechanism action blockade de novo pyrimidine biosynthesis by inhibition dihydroorotic dehydrogenase. In vitro studies demonstrate the superiority prolonged drug exposure achieving growth inhibition. This phase I study evaluated administration brequinar short, daily i.v. infusion for 5 days repeated every 4 weeks. Fifty-four subjects were enrolled received doses ranging from 36–300 mg/m2. The dose-limiting toxicities mucositis diffuse skin rash. Other included myelosuppression, nausea, vomiting, malaise, burning at site. maximum tolerated dose on “daily times 5” schedule was 300 recommended II 250 Pharmacokinetic analysis day 1 clearance curves 51 showed slight nonlinearity relationship between area under curve (AUC). versus AUC well described using Michaelis-Menten model elimination kinetics with V max = 45 (µg/ml)/h K m 123 µg. Analysis revealed diminution to 30 (µg/ml)/h. As consequence reduction max, plasma concentrations higher than predicted kinetics. Pharmacodynamic kinetic parameters occurring during first cycle therapy significant correlations dose, AUC, peak concentration; leukopenia thrombocytopenia β rate.