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The pharmacokinetics of TNP-470, a new angiogenesis inhibitor
W D Figg1, J M Pluda, R M Lush
1Clinical Pharmacokinetics Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
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.
Insights
TNP-470, an angiogenesis inhibitor, showed linear pharmacokinetics in patients with Kaposi's sarcoma. The drug was rapidly cleared, suggesting continuous infusion may enhance efficacy for solid tumors.
Area of Science:
- Pharmacology and Oncology
- Clinical Trial Design and Analysis
Background:
- TNP-470 is a synthetic analog of fumagillin with potent anti-angiogenic properties.
- It has demonstrated efficacy in inhibiting neovascularization in preclinical solid tumor models.
Purpose of the Study:
- To characterize the pharmacokinetic profile of TNP-470 in patients.
- To evaluate the relationship between TNP-470 dosage and its concentration in plasma.
Main Methods:
- A dose-escalation Phase I clinical trial was conducted at the National Institutes of Health.
- Thirteen sequential cohorts of patients with HIV-associated Kaposi's sarcoma received TNP-470 via 1-hour intravenous infusion.
- Pharmacokinetic parameters were determined using reverse-phase high-performance liquid chromatography.
Main Results:
- A linear correlation was observed between TNP-470 dose and both AUC(inf) and Cmax.
- Peak plasma concentrations (Cmax) ranged from 6.6 ng/ml to 597.1 ng/ml across the tested dosages.
- The drug exhibited rapid clearance with a short terminal half-life (0.88 ± 2.5 hr), and its active metabolite, AGM-1883, showed peak concentrations between 0.4 and 158.1 ng/ml.
Conclusions:
- Achievable in vivo concentrations of TNP-470 reached levels with in vitro activity.
- Rapid clearance after a single infusion was noted, with significant interpatient variability but no saturable elimination.
- Continuous infusion of TNP-470 may be a viable strategy if prolonged exposure is required for therapeutic effect.