Dose investigation of imrecoxib in patients with renal insufficiency based on modelling and simulation.

OBJECTIVE:Imrecoxib is a new moderately selective cyclooxygenase-2 (COX-2) inhibitor. A previous study has shown that drug exposure differs significantly in renally impaired patients. We aim to describe the population pharmacokinetics (PPK) of imrecoxib (M0) and its two metabolites (M1, M2) to provide a theoretical basis for investigating imrecoxib doses for renally impaired patients. METHODS:Using PPK analysis, 24 patients with 257 different plasma concentrations were studied. Of these, 12 had severe renal impairment and 12 had normal renal function. The dose regimen was simulated based on the final model to compare the ratio (Cu,ss/IC50) of the average unbound concentration at steady state (Cu,ss) to the half-maximal inhibitory concentration (IC50) of COX-2. RESULTS:Imrecoxib and its metabolite concentrations were satisfactorily described by a two-compartment with first-order transit absorption model for imrecoxib and a one-compartment model for its metabolites. Renal function was a significant binary covariate. Scenarios of '75 mg q12h' and '50 mg q8h' in renally impaired patients had similar Cu,ss/IC50 values with a '100 mg q12h' regimen in subjects with normal renal function. CONCLUSION:A PPK model of imrecoxib and its two metabolites is presented. The renal insufficiency regimen should be reduced to '75 mg q12h' or '50 mg q8h'.