The Pharmacokinetics of TNP‐470, a New Angiogenesis Inhibitor

摘要: Study Objective. To characterize the pharmacokinetic profile of TNP-470, a synthetic analog fumagillin that is potent inhibitor angiogenesis and inhibits neovascularization in several solid tumor models. Design. A dose-escalation phase I clinical trial. Setting. The National Institutes Health. Patients. Patients with human immunodeficiency virus-associated Kaposi's sarcoma. Interventions. TNP-470 dosage was increased 13 sequential cohorts using modified Fibonacci escalation scheme (4.6, 9.3, 15.4, 23.2, 43.1 mg/m2). drug administered as 1-hour intravenous infusion. Serial blood samples were collected assayed by reverse-phase high-performance liquid chromatography pharmacokinetics characterized. Measurements Main Results. There linear relationship between dose both area under curve to infinity (AUC[inf]) time maximum concentration (Cmax). Cmax ranged 6.6 ng/ml at lowest (4.6 mg/m2) 597.1 highest (43.1 agent rapidly cleared from circulation short terminal half-life (0.88 ± 2.5 hr), which consistent preclinical data. Peak plasma concentrations AGM-1883, an active metabolite, 0.4 158.1 ng/ml. Conclusion. Concentrations have vitro activity achievable vivo. after single considerable interpatient variability clearance, but no evidence saturable elimination. If more prolonged exposure necessary for activity, administration continuous infusion may be suitable.