We investigated the safety, tolerability, pharmacokinetics and pharmacologicaleffects of MK-954, a new angiotensin II receptor antagonist, in healthy male volunteersafter oral administration of 100 mg once daily for 7 days.
Nine subjects were randomly divided into 2 groups (active drug 6, placebo 3). On the1st and 7th days, the test drug was administered in the fasted state (before breakfast), and on 2-6th days, it was administered after breakfast. The results were as follows: (1) A decrease in blood pressure was observed in the active drug group after 6 hoursfollowing the first drug administration.(2) Some adverse experiences such as headacheand dizziness on standing up were observed after MK-954 administration; these experiences were mild and transient. In laboratory findings, a decrease of serum uric acid wasobserved after MK-954 administration. No other abnormal laboratory findings wereobserved.(3) Mean Tmax of MK-954 and its active metabolite E-3174 were 0.8 and 2.3 hr, respectively. MK-954 disappeared quickly from the plasma with a t1/2 of about 2 hr ; the t1/2 of E-3174 was 5 hr. There was no significant difference in the Cmax and AUC of MK-954 and E-3174 between the first and the 7th days, suggesting a lack of accumulation of MK-954.(4) Serum uric acid decreased and the urinary excretion of uric acid increasedduring MK-954 treatment. The mechanism underlying the uricosuric effect remainedundefined.
In conclusion, it was demonstrated that 100 mg of MK-954 is safe for a 7-day dosageperiod with no accumulation in healthy male volunteers. Based on these results, 100 mgwas recognized as appropriate for the maximum dose in the proceeding early phase IIstudies.
