Pharmacology of enflicoxib, a new coxib drug: Efficacy and dose determination by clinical and pharmacokinetic-guided approach for the treatment of osteoarthritis in dogs based on an acute arthritis induction model.

Abstract

Enflicoxib is a newly developed NSAID of the coxib class. The optimal therapeutic dose to be confirmed in the field studies was established using a combination of pharmacokinetic (PK) modelling and pharmacodynamic (PD) studies. First, a PK study was performed to determine the plasmatic profile of enflicoxib and its active pyrazol metabolite in dogs. Thereafter, two studies using a urate crystal‐induced acute arthritis model allowed to correlate efficacy with plasmatic concentrations. Finally, a population PK model was developed to establish the Minimum Effective Concentration (MEC) and the Maximum Tolerated Concentration (MTC). Enflicoxib plasma concentrations were highest for the first 48 h. Thereafter, pyrazol metabolite concentrations were higher and persisted up to the end of the study. No reduction on the lameness (CLS) or pain scores (PS) was observed in the first hours after enflicoxib administration so no MEC could be established for the parent compound. Both CLS and PS were greatly reduced when the pyrazol metabolite achieved concentrations of 411 ng/ml or higher, so this concentration was established as the MEC for the pyrazol metabolite. Enflicoxib MTC was established at 6723 ng/ml whereas for the pyrazol metabolite it was 4258 ng/ml. The population PK model showed that a loading enflicoxib dose of 8 mg/kg followed by weekly maintenance doses of 4 mg/kg would achieve stable concentrations of the pyrazol metabolite within the therapeutic window (between the MEC and the MTC), and it was considered the most adequate posology to be confirmed in the field clinical studies for the treatment of canine osteoarthritis.