Pharmacokinetics of enflicoxib in dogs: Effects of prandial state and repeated administration

The pharmacokinetics of enflicoxib were evaluated in both a bioavailability study and a multi‐dose safety study in Beagle dogs. When administered at 8 mg/kg, the oral bioavailability (F) of enflicoxib was 44.1% in fasted dogs, but F increased to 63.4% under post prandial conditions. Enflicoxib is rapidly metabolised. After the first 48 h, the plasma levels of its pyrazol metabolite were much higher and persistent than those of the parent compound. Following intravenous administration, the total body plasma clearance of enflicoxib was of 140 ml/h/kg and the volume of distribution based on the terminal phase was 4 L/kg. Plasma protein binding for both compounds was approximately 99%. The blood to plasma ratio for the pyrazol metabolite showed saturable kinetics with higher blood cell affinity at lower total blood concentrations which ranged from 2.49 to 0.95 for concentrations from 1 to 15 µg/ml. Enflicoxib and its pyrazol metabolite exhibited dose‐proportional pharmacokinetics for single oral doses of 8–40 mg⁄kg and for multiple oral doses of 4–20 mg⁄kg. After 7 months of repeated weekly administrations, pre‐dose plasma concentrations (C(min,ss)) remained constant throughout the study, with no trend to any significant over‐accumulation. The mean terminal elimination half‐life (t(½)) was 20 h for enflicoxib and 17 days for the pyrazol metabolite. The pharmacokinetic profile of enflicoxib and its pyrazol metabolite in dogs supports the proposed dosing regimen in which doses are separated by 1 week.