Ｐｉｒｍｅｎｏｌ ｈｙｄｒｏｃｈｌｏｒｉｄｅ （ＣＩ‐８４５）の第１相臨床試験

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Safety, tolerance and pharmacokinetics of pirmenol hydrochloride (pirmenol), a new antiarrhythmic agent, were investigated in 21 healthy male volunteers following single oral dose of 25, 50, 100, 200mg or placebo and in 5 subjects following multiple oral doses of 100mg b. i. d. for 7 days. At the same time, effect of food intake on the kinetics of pirmenol was determined in 5 subjects following a single 100mg dose at fasting and 30min after breakfast.No remarkable change was observed in the blood pressure, body temperature and clinical laboratory data. As subjective symptoms, headache, heaviness in the head, chest discomfort etc. were observed after the drug and placebo administration, but were slight, transient and dose-independent.Increase of the pulse rate and prolongation of QTc were noted following single and multiple doses. PR intervals and QRS duration were prolonged at the highest 200mg dose. Decrease in the ejection fraction and fractional shortening without obvious change in cardiac index was observed at a single 200mg dose.The peak plasma concentration (Cmax) and the area under the time-concentration curve (AUC) increased in a dose-dependent manner. Cmax after 25, 50, 100 and 200mg dose occurred within 1.2 to 1.5hr and were 0.21, 0.35, 0.86 and 1.77μg/ml, respectively, and plasma half-life of the β-phase (t1/2β) was the range of 7.4 to 13.8hr under fasting state. Twenty-four hr cumulative urinary excretion of unchanged pirmenol was 15-23%.Administration of pirmenol with food slightly delayed the rate and decreased the extent of the absorption, but there was no significant difference between the fasted and fed states.After the start of multiple dosing, steady-state plasma pirmenol concentrations were attained by Day 3 and Cmax was 60% higher at the steady-state than on Day 1.We concluded that these findings showed that oral pirmenol is well tolerated within the dose-range used in this study and can be expected to have clinical efficacy in patients with various cardiac arrhythmias.