Pharmacokinetic and Pharmacodynamic Profiles of Vapiprost, a Selective, Long‐Lasting Thromboxane Receptor Antagonist, After Single and Multiple Oral Administration to Healthy Volunteers
Authors: Uematsu Toshihiko , Nagashima Satoru , Mizuno Atsuhiro , Hirano Keiko , Nakashima Mitsuyoshi 
Published: March 2013

A selective thromboxane A2 (TXA2) receptor blocking agent, vapiprost, was orally administered to healthy male Japanese volunteers to investigate the pharmacokinetic and pharmacodynamic properties. The time‐profile of vapiprost concentration in plasma was determined and the effects of the drug on platelet aggregation in platelet‐rich plasma (PRP) induced by a stable TXA2 receptor agonist U‐46619, adenosine diphosphate (ADP) and collagen, and platelet aggregation in whole blood induced by U‐46619 ex vivo were simultaneously examined and compared. In the single‐dose study (5, 10, and 20 mg/man) the plasma concentrations of the drug were fitted well to a one‐compartment open model with a first‐order absorption. The area under plasma concentration‐time curve (AUC) and maximum plasma concentration (Cmax) showed dose‐related increases, whereas the mean elimination half‐lives (t1/2) remained approximately constant within the range of 0.99–1.1 hour. The drug was hardly recovered unchanged in urine. The platelet aggregation in PRP induced by collagen or U‐46619 and the secondary aggregation by ADP were inhibited; that induced by U‐46619 was the most specifically and completely inhibited at 2 hours after administration of any dose. The duration for maintaining the significant inhibition tended to depend on the dose and ranged from 24 to 36 hours after administration, which was much longer than expected from the plasma concentration of drug. The time‐profile of inhibiting whole blood platelet aggregation that was induced by U‐46619 was almost parallel to that of platelet aggregation in PRP by the same aggregant. The bleeding time was slightly prolonged 2 and 8 hours after administrations of 10 and 20 mg, respectively. In the multiple‐dose study (20 mg/man twice daily for 5 days; 9 doses in total) plasma concentration of the drug after each administration showed a good conformity with the simulation curve worked out using the pharmacokinetic parameters that were obtained at the time of the initial dose. This indicated that repeated administrations did not result in accumulation. Throughout the administration period, almost the same extent of inhibiting platelet aggregation by each aggregant was maintained. After the final administration almost complete inhibition of platelet aggregations both in PRP and whole blood by U‐46619 was maintained till 48 hours and a significant inhibition lasted over 72 hours, which also surpassed the duration of maintaining plasma concentration. The bleeding time showed no significant prolongation. No abnormality attributable to the test drug was found in the routine laboratory tests, subjective and objective findings, vital signs including blood pressure, pulse rate, and body temperature, and ECG except that one of six subjects in the multiple‐dose study showed a slight elevation of liver function test parameters. Drug administration was discontinued in this subject after the eighth dose. These parameters returned to the normal values within 1 week after the discontinuation. In conclusion, oral administration of vapiprost was well‐tolerated with long‐lasting inhibition of platelet aggregation both in PRP and whole blood.