POPULATION ANALYSIS OF THE PHARMACOKINETICS AND PHARMACODYNAMICS OF SERATRODAST IN PATIENTS WITH MILD-TO-MODERATE ASTHMA

Background: Seratrodast, a potent thromboxane receptor antagonist, is approved in Japan for the treatment of asthma and currently is being d eveloped in the United States. Methods: This was a phase II, randomize d, double-blind, parallel-group, placebo-controlled 15-center study of seratrodast in patients with mild to moderate asthma, A total of 183 patients mere randomly assigned to receive daily doses of either place bo, or 80 mg seratrodast, or 120 mg seratrodast for 8 weeks, Pharmacok inetic and pharmacodynamic modeling was carried out by means of the po pulation approach, A two-compartment model with zero-order input and f irst-order elimination best fitted the plasma concentration-time data. Results and conclusion: The pharmacokinetics of seratrodast were line ar after single and multiple dosing for 8 weeks, The population estima tes for oral clearance and apparent volume of distribution were 8.5 ml /hr/kg and 43.3 ml/kg, respectively, All pharmacokinetic parameters (t he oral central compartment clearance, the volumes of distribution of the central and peripheral compartments, and the intercompartmental cl earance) were estimated with a precision of 10% or less and were found to be associated with body weight, The residual variability was 30%, The values of oral clearance estimated In this study in male patients were similar to those previously estimated in healthy male subjects, S eratrodast at a dose of 120 mg daily produced an increase in forced ex piratory volume in 1 second (FEV1) from baseline that was linearly cor related with its plasma concentrations, The average slope of the conce ntration-effect relationship was 0.222% and 0.470% per mu g/ml after s ingle and multiple dosing, respectively. Interpatient variability in r esponse was mainly affected by the initial severity of the disease, A lower percentage of predicted FEV1 (i.e., more severe obstruction) was associated with higher slopes, and greater increases in FEV1.