Pharmacokinetics and Dose Range-Finding of Benzoic Acid, 2-Chloro-5-(((5,6-Dihydro-2-Methyl-1,4-Oxathiin-3-YL)Carbonyl) Amino)-1-Methylethyl Ester (NSC-D615985) in Beagle Dogs

摘要

The purpose of the study was to determine the plasma elimination kinetics of NSC-D615985 and to evaluate the potential for acute toxicity after intravenous and oral administration in the beagle dog. Two dogs/group (1/sex) were dosed with 5 (Group 1) or 10 (Group 2) mg/Kg of NSC-D615985 on Study Day 1 (IV). On Study Day 8, dogs received 100 (Group 1) and 750 (Group 2) mg/Kg (PO). Blood was collected at the following time intervals following each treatment: 0, 2, 5, 10, 20, 30, 60, 90, and 120 (minutes); 4, 8, 12, 16, 20, and 24 (hours). Measured formulated dose concentrations were 0.338 and 0.875 mg/mL compared to target doses of 0.5 and 1.0 mg/mL for the IV doses. The measured formulated oral dose concentrations were 4.47 and 60.29 mg/mL compared to 10 and 75 mg/mL, respectively. Plasma concentrations of the test article in Dog M1 (Group 1) which was treated with 5.0 mg/Kg of NSC-D615985 were near the limit of detection within 2 minutes after IV dosing, while no detectable plasma levels were found at any sampling times in Dog F3 from the same dose group. In Dogs M2/F4 treated with 10.0 mg/Kg, IV, measurable plasma levels were observed 10 minutes after dose administration at similar concentrations. In the oral dosing phase of the study, plasma concentrations of the test article were below quantifiable detection limits in both groups of dogs and the extrapolated values were not considered reliable for determining elimination kinetics. The variability observed in the results between dose groups and exposure routes may have been due, in part, to an interaction of the drug with the vehicle.