The pharmacokinetics of TNP-470, a new angiogenesis inhibitor

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