Pharmacokinetics of orally administered carboxyamido-triazole, an inhibitor of calcium-mediated signal transduction.
Carboxyamido-triazole (CAI), inhibits proliferation, invasion, and metastatic potential of a number of cancer cell lines at concentrations greater than 0.4 microgram/ml. The objective of this study was to characterize the pharmacokinetic profile from the first Phase I clinical trial of CAI for the single test dose and multiple daily dosing schedule. Two different p.o. formulations (liquid and gelcap) of CAI were administered. Thirty-nine patients with cancer were enrolled. The dose escalation schema was 100, 125, and 150 mg/m2/day and 200 and 330 mg/m2 every other day of the liquid formulation, plus 100 and 125 mg/m2/day and 200 mg/m2 every other day of the gelcap. The CAI pharmacokinetics are best described by a two-compartment open linear model. The gelcap was more rapidly absorbed than the liquid [time to maximum plasma concentration (Tmax) = 2.06 +/- 1.02 versus 5.31 +/- 3.59 h, P2 = 0.0012] which resulted in higher peak plasma concentrations. There was no evidence of saturable elimination as the dose was increased. The mean steady-state peak concentration was 5.1 +/- 1.0 microgram/ml for the 150 mg/m2/day multiple daily dosing regimen. The terminal half-life of CAI was relatively prolonged, 111 h, and the total body p.o. clearance was low (1.87 liters/h). The peak concentration for all dose levels explored was greater than the targeted concentration suggested by in vitro data for activity. Thus, these data suggest that an effective cytostatic exposure of CAI may be obtained with daily or every other day dosing without severe toxicity.
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W D
WD
Clinical Pharmacology Branch and the Signal Transduction and Prevention Unit, Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Cole
K A
KA
Reed
E
E
Steinberg
S M
SM
Piscitelli
S C
SC
Davis
P A
PA
Soltis
M J
MJ
Jacob
J
J
Boudoulas
S
S
Goldspiel
B
B
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D002118:Calcium / Q000378:metabolism; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D015398:Signal Transduction; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D014230:Triazoles; C062058:carboxyamido-triazole; D002118:Calcium