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 (Cmax). The Cmax 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.