Characterization of the pharmacokinetics and pharmacodynamics of a new oral thromboxane A2-receptor antagonist AA-2414 in normal subjects: population analysis

• Published in: Clinical pharmacology and therapeutics Vol. 55; no. 4; p. 441
• Main Authors: Hussein, Z, Samara, E, Locke, C S, Orchard, M A, Ringham, G L, Granneman, G R
• Format: Journal Article
• Language: English
• Published: United States 01.04.1994
• Subjects: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Oral; Adolescent; Adult; Benzoquinones; Body Weight; Double-Blind Method; Heptanoic Acids; Humans; Leukotriene B4 - blood; Male; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - pharmacology; Prostaglandin Endoperoxides, Synthetic - pharmacology; Quinones - administration & dosage; Quinones - blood; Quinones - pharmacokinetics; Quinones - pharmacology; Receptors, Thromboxane - antagonists & inhibitors; Thromboxane A2 - analogs & derivatives; Thromboxane A2 - pharmacology; Thromboxane B2 - blood
• ISSN: 0009-9236
• DOI: 10.1038/clpt.1994.54

The pharmacokinetics and pharmacodynamics of AA-2414 [(+-)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptano+ ++ ic acid] were evaluated in 39 healthy male subjects after four different oral multiple-dosing 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 A2 mimetic, was significantly inhibited by AA-2414. The effect was found to be linearly related to plasma concentration with population estimates of 2.3 mumol/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 B4, thromboxane B2, and anti-platelet aggregation factor activity measurements were not significantly affected by administration of AA-2414.