Characterization of the pharmacokinetics and pharmacodynamics of a new oral thromboxane A2-receptor antagonist AA-2414 in normal subjects: population analysis.
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.
Hussein
Z
Z
Department of Pharmacokinetics and Biopharmaceutics (D-4PK), Abbott Laboratories, Abbott Park, IL 60064.
Samara
E
E
Locke
C S
CS
Orchard
M A
MA
Ringham
G L
GL
Granneman
G R
GR
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D016227:Benzoquinones; D001835:Body Weight; D004311:Double-Blind Method; D006538:Heptanoic Acids; D006801:Humans; D007975:Leukotriene B4 / Q000097:blood; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011809:Quinones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D013929:Thromboxane B2 / Q000097:blood
D016227:Benzoquinones; D006538:Heptanoic Acids; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D011809:Quinones; D017482:Receptors, Thromboxane; D007975:Leukotriene B4; C060230:seratrodast; D013929:Thromboxane B2; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid