The pharmacokinetics of TNP-470, a new angiogenesis inhibitor.
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.


METHODS
A dose-escalation phase I clinical trial.


METHODS
The National Institutes of Health.


METHODS
Patients with human immunodeficiency virus-associated Kaposi's sarcoma.


METHODS
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.


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.


CONCLUSIONS
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.
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WD
Clinical Pharmacokinetics Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Pluda
J M
JM
Lush
R M
RM
Saville
M W
MW
Wyvill
K
K
Reed
E
E
Yarchoan
R
R
D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003510:Cyclohexanes; D015658:HIV Infections / Q000150:complications*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D012514:Sarcoma, Kaposi / Q000098:blood supply* / Q000188:drug therapy / Q000209:etiology; D012717:Sesquiterpenes / Q000493:pharmacokinetics* / Q000627:therapeutic use
D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D012717:Sesquiterpenes; D000077609:O-(Chloroacetylcarbamoyl)fumagillol