CHARACTERIZATION OF THE PHARMACOKINETICS AND PHARMACODYNAMICS OF A NEW ORAL THROMBOXANE A(2)-RECEPTOR ANTAGONIST AA-2414 IN NORMAL SUBJECTS- POPULATION ANALYSIS

The pharmacokinetics and pharmacodynamics of AA-2414 -trimethyl-1,4-be nzoquinon-2-yl)-7-phenylheptanoic acid] were evaluated in 39 healthy m ale subjects after four different oral multiple-dosing regimens. Popul ation pharmacokinetic analysis with NONMEM showed plasma concentration -time profiles of AA-2414 to be best characterized by a two-compartmen t open model with zero-order input and first-order elimination. The fi nal estimates for oral clearance, volume of distribution, and steady-s tate volume of distribution were 10.7 ml/hr/kg, 92.8 ml/kg, and 280 ml /kg, respectively; the corresponding coefficients of variation for int erindividual variability were 21%, 10%, and 9%. The pharmacokinetic pa rameters were associated only with body weight. The residual variabili ty was 25%. The ex vivo platelet aggregation response to U-46619, a th romboxane A(2) mimetic, was significantly inhibited by AA-2414. The ef fect was found to be linearly related to plasma concentration with pop ulation estimates of 2.3 mu mol/L and 2.38 for the baseline effect and slope, respectively; the corresponding coefficients of variation for interindividual variability were 22% and 38%. The residual variability was 39%. The leukotriene B-4, thromboxane B-2, and anti-platelet aggr egation factor activity measurements were not significantly affected b y administration of AA-2414.