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 [(±)‐7‐(3,5,6‐trimethyl‐l,4‐benzoquinon‐2‐yl)‐7‐phenylheptanoic acid] were evaluated in 39 healthy male subjects after four different oral multipledosing regimens. Population pharmacokinetic analysis with NONMEM showed plasma concentration–time profiles of AA‐2414 to be best characterized by a two‐compartment open model with zero‐order input and first‐order elimination. The final estimates for oral clearance, volume of distribution, and steady‐state volume of distribution were 10.7 ml/hr/kg, 92.8 ml/kg, and 280 ml/kg, respectively; the corresponding coefficients of variation for interindividual variability were 21%, 10%, and 9%. The pharmacokinetic parameters were associated only with body weight. The residual variability was 25%. The ex vivo platelet aggregation response to U‐46619, a thromboxane A 2 mimetic, was significantly inhibited by AA‐2414. The effect was found to be linearly related to plasma concentration with population estimates of 2.3 µmol/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 aggregation factor activity measurements were not significantly affected by administration of AA‐2414. Clinical Pharmacology and Therapeutics (1994) 55, 441–450; doi: 10.1038/clpt.1994.54