title: Influence of age on the pharmacokinetics of vapiprost, a thromboxane A2 receptor antagonist, and platelet aggregation: comparison of pharmacokinetics by routine approach and population pharmacokinetics.
abstract: The effects of a single-dose oral administration of a thromboxane A2 receptor antagonist, vapiprost (SN-309), on pharmacokinetic profile and inhibition of platelet aggregation were investigated in six healthy elderly volunteers (age: 65-72 years) and the influence of age on these parameters was studied by comparison with the results obtained in phase-I data involving healthy young participants. Although direct comparison of pharmacokinetic parameters was inappropriate because of different models, high Cmax and AUC values were obtained on comparison with the young. The inhibition of platelet aggregation in platelet rich plasma induced by U-46619 or collagen was rapidly established and remained suppressed for more than 8 h, although the effect was short-acting compared with the inhibition period in the young. This suggests that dose adjustment in the elderly is unnecessary In addition to a routine pharmacokinetic approach to determine the time-profile of vapiprost, population pharmacokinetics were studied using data from 51 volunteers in five clinical trials including the two above-mentioned studies. By fitting 812 plasma-monitoring points into the two-compartment model, the effects of several factors including age on parameters were investigated, based on the nonlinear mixed effect model. Clearance in the elderly attenuated 82.2% of that in the young, the distribution volume varied with platelet counts and delayed absorption was observed in volunteers with, rather than without, food intake. Closer bridging studies with other countries have resulted in the current local situation of abbreviating phase-III studies. Consequently to clarify the pharmacokinetic profile of the elderly in Japan and other countries, the population pharmacokinetics approach based on the data in the various phase I-II trials is useful.
authors.affiliation: Clinical Pharmacology Center, Nippon Medical School, Tokyo, Japan. kaz@nms.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Ohashi
authors.forename: R
authors.initials: R
authors.lastname: Aso
mesh_terms: D000368:Aged; D000375:Aging / Q000378:metabolism*; D000465:Algorithms; D019540:Area Under Curve; D001713:Biphenyl Compounds / Q000009:adverse effects / Q000493:pharmacokinetics*; D003094:Collagen / Q000494:pharmacology; D006207:Half-Life; D006538:Heptanoic Acids / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D017711:Nonlinear Dynamics; D010974:Platelet Aggregation / Q000187:drug effects*; D011153:Population; D011448:Prostaglandin Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics*; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*
chemical_list: D001713:Biphenyl Compounds; D006538:Heptanoic Acids; D011448:Prostaglandin Antagonists; D017482:Receptors, Thromboxane; D003094:Collagen; C060013:vapiprost