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/m 2 ). 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/m 2 ) and 597.1 ng/ml at the highest dosage (43.1 mg/m 2 ). 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.