Pharmacokinetic and Pharmacodynamic Profiles of CS‐518, A Selective, Long‐Lasting Thromboxane Synthase Inhibitor, After Single and Multiple Oral Administration to Healthy Volunteers

A selective thromboxane (TX) synthase inhibitor, CS‐518, was orally administered to healthy male Japanese volunteers and the pharmacokinetic and pharmacodynamic properties were investigated. The time profile of drug concentrations in plasma was determined, and the effects of the drug on platelet aggregation in plasma induced by arachidonic acid (AA) and adenosine diphosphate (ADP) ex vivo were examined. The production of TXB 2 and 6‐keto‐prostaglandin F 1 α (6‐keto‐PGF 1 α) in serum during whole Wood coagulation ex vivo also were examined. In the single‐dose study (50, 100, and 200 mg), plasma concentrations of the drug were well fitted to a one‐compartment open model with first‐order absorption. The area under plasma concentration curve (AUC) and maximum plasma concentration (Cmax) showed dose‐related increases, whereas the mean elimination half‐lives remained rather constant (.68‐.92 hour). The drug was recovered in urine by 32 to 37% and 62 to 65% as unchanged and conjugated forms (acylglucuronide), respectively, showing almost complete absorption of CS‐518. The effect of food intake on the pharmacokinetics of CS‐518 was determined at the dose of 100 mg. The time to reach Cmax was prolonged from .42 to 2.08 hours and the Cmax was decreased by about 66%, whereas the AUC and urinary recovery showed no significant changes. The platelet aggregation in plasma induced by AA was markedly inhibited, whereas the secondary aggregation induced by ADP was inhibited to a much less degree. Platelet aggregation by AA was almost completely inhibited 2 hours after administration of any dose and the duration for maintaining the significant inhibition tended to depend on the dose ranging from 48 to 72 hours after administration, which was much longer than expected from the plasma concentration of drug. The inhibition of TX synthase was more markedly shown in the decreased production of TXB 2 and reciprocally increased production of 6‐keto‐PGF 1 α in serum during whole blood coagulation, which peaked at 1 hour and lasted until 3 to 7 days after administration, depending on the dose. In the multiple‐dose study (100 mg, twice daily, for 4.5 days), drug concentrations in plasma after each administration showed a good conformity with the simulation curve worked out using the pharmacokinetic parameters obtained after the initial dose, indicating that repeated administrations did not result in accumulation. Throughout the administration period, almost complete inhibition of platelet aggregation by AA was maintained and continued until 48 hours after the last administration, and a significant inhibition lasted more than 72 hours, which appeared much longer than expected from the plasma concentration of CS‐518. 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 electrocardiogram. Oral administration of CS‐518 was concluded to be well tolerated with long‐lasting inhibition of TX synthase in platelet.