Phase I Study of MK-954, a New Angiotensin II Receptor Antagonist. Results of Single Oral Administration.

We investigated the safety, tolerability, pharmacokinetics and pharmacologicalprofile of MK-954, a new angiotensin II receptor antagonist, in healthy male volunteersafter single oral administration.Twenty-four subjects were divided into 4 groups (6 subjcts/group) and were given MK-954 (25, 50, 100 or 200 mg) after an overnight fast, followed by 100 mg afterbreakfast. The results were as follows: (1) Modest decreases in blood pressure occurredafter the administration of MK-954. Heart rate was increased slightly, but, dose dependency was not observed.(2) Signs and symptoms such as headache (n=3), feeling hot (n=1), orthostatic hypotension (n=4) and dizziness (n=1) were observed after MK-954administration these experiences were mild and transient. Abnormal laboratory findings such as increased serum creatinine (n=1) and decreased serum uric acid (n=1) were observed with the highest dose.(3) Mean plasma concentrations of MK-954 and itsactive metabolite E-3174 after dosing in the fasted state reached their peaks at 0.7-1.3and 2.0-3.7 hr, respectively, then diminished with a t1/2 of 1.5-2.5 and 3.8-4.4hr, respectively. The Cmax of MK-954 and E-3174 which exhibited dose dependency were 84.5-1394 .9 and 188.9-2219.0 ng/ml respectively, and their AUCs, also dose dependent, were201.3-2231.2 and 1348.9-10861.4ng⋅hr/ml, respectively. Although a decreased Cmax andprolonged Tmax were observed in the fed state, the AUC of MK-954 and E-3174 were 80%and 86%, respectively, of those obtained with the same dose in the fasted state, indicatingno difference in total systemic absorption between the fasted and fed state.(4) Serum uricacid decreased and urinary excretion of uric acid increased in a dose dependent mannerand without effects on urinary creatinine excretion. These findings suggest that MK-954has uricosuric effects.In conclusion, it was demonstrated that single doses of 100 mg of MK-954 and lowerwould be safe and desirable to administer, because orthostatic hypotension was observedat the highest dose (200 mg).