Phase I Study of Y‐20811, a New Long‐Acting Thromboxane Synthetase Inhibitor by Oral Administration

The safety, pharmacological action and pharmacokinetics of the thromboxane (TX) synthetase inhibitor Y‐20811, a prospective medication for ischemic vascular disorder, were investigated in Phase I clinical trials in which single and repeated doses were administered orally to 32 healthy adult male volunteers. In the single‐dose study, subjects were given single doses of 2.5, 5, 10, 25, 50, and 100 mg; in the repeated‐dose study, a single dose of 50 mg was administered daily for 5 days. In the repeated‐dose study, slight elevation of liver function test parameters in 1 subject was observed, but throughout the trials, no abnormality attributable to the test drug was found in other routine laboratory tests, subjective and objective findings, vital signs (blood pressure, pulse rate, body temperature, respiration rate), ECG, or bleeding time; nor did any finding indicate a problem concerning the safety of Y‐20811. In both single‐ and repeated‐dose studies, inhibition of the serum TXB 2 production and an increase in the 6‐keto‐prostaglandin F 1 α production during whole‐blood coagulation, and inhibition of arachidonic acid‐induced platelet aggregation were observed from 1 hour after administration of Y‐20811. The duration of these actions was long, the former two lasting 168 hours (1 week) and the latter 48–72 hours or more. Slight inhibition of adenosine diphosphate‐induced secondary platelet aggregation was also observed. The maximum plasma concentration time (t max ) of Y‐20811 was 0.5–1.1 hours. The initial‐phase half‐life (t 1/2 α) was 0.8–1.1 hours and the final‐phase half‐life (t 1/2 β) was 4.7–9.2 hours. Maximum plasma concentration (C max ) and the area under the plasma concentration‐time curve (AUC) increased dose‐dependently. When Y‐20811 was administered after a meal, t max was delayed and C max was decreased, but there was almost no change in AUC. In the repeated‐dose study, plasma concentrations after each administration showed a good conformity with the simulation curve worked out using the pharmacokinetic parameters obtained at the time of the initial dose, indicating that repeated administration did not result in accumulation of the drug. In all dose groups, 47–62% of the dose was excreted in unchanged form and 8–14% was excreted in conjugated form in the urine within 48 hours after administration. No daily change was observed in the 24‐hour urinary excretion with repeated administration. The duration of pharmacological action did not parallel the change in plasma concentration. Oral administration of Y‐20811 was concluded to be safe and well‐tolerated with long‐acting inhibition of the serum TXB 2 production and platelet aggregation.