Pharmacokinetics and Pharmacodynamics of Moracizine (EN-313) in Healthy Japanese Volunteers.

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We administered single oral doses of 100, 200, 300 and 400 mg of EN-313 and repeated oral doses of 300 mg t.i.d., for 1 and 7 days to healthy adult men to confirm the safety and pharmacokinetics of this agent and to elucidate the effect of meals on the pharmacokinetics at a dose of 300 mg. At single doses of 100 and 200 mg, there were subjective symptoms of dizziness and nausea, but these were slight, and were regarded to have no relation to the test agent. No objective symptom was observed. And there was no abnormal finding in blood pressure, pulse rate, body temperature, or the results of laboratory tests. There was no significant change in the ECG parameters or in the hemodynamic parameters obtained by echocardiogram. After oral administration, EN-313 was rapidly absorbed, and reached Cmax in 0.77-1.17 hrs. EN-313 disappeared in two phases, and its T1/2 was 2. 21 to 3.08hrs. EN-313 showed a linear increase in Cmax and AUC concomitant with the dose increase. The Tmax of EN-313 was prolonged from 0.97 to 1. 45 hrs when administered after breakfast. The rates of excretion of the compounds in the urine were less than 1% (EN-313, 0.04%; INX-5575, 0. 51%; INS-9673, 0. 206%), even at the dose of 400mg. In the repeat-dose study, subjective/objective symptom, blood pressure, body temperature and laboratory test data indicate no abnormal change considered to be caused by EN-313. However, in the seven-day test, a significant increase in pulse rate was observed from day 4 of administration. ECGs revealed shortened RR on QT intervals and a prolonged PQ interval, but no significant change was observed QRS width or in QTc. No significant change was observed in hemodynamic parameters. In the one-day test, the Tmax of EN-313 after the first administration was 1.5 hrs and the Cmax was 0.728 μg/ml. After the second administration, Tmax doubled and Cmax was 0.482 μg/ml. Cmax after the third administration was lower than after the second. Twelve hrs after the third administration, the concentration of EN-313 was only approximately 0.05 μg/ml, with no drug accumulation. And in the seven-day test, the Cmax of EN-313 was 0.465μg/ml on day 1, and was at a similar level on day 4, but on day 7 it was decreased to 0.288μg/ml. The AUC of EN-313 was 1.48μg/ml on day l and 1.519μg/ml on day 4, then on day 7 it fell to 0.893μg/ml, but the difference between the day 1 and 7 values was not statistically significant. Tmax for EN-313 were 3. 17, 1. 83 and 3. 67 hrs on days 1, 4 and 7, respectively. No accumulation of EN-313 was seen throughout the 7- day oral administration. The total excreted amount of EN-313, INX-5575 and INX-9673 was less than 1%. The above results demonstrate the safety of EN-313 for clinical use; no problems have arisen during a 7-day period of multiple-dose administration.
一般社団法人日本臨床薬理学会の論文

Pharmacokinetics and Pharmacodynamics of Moracizine (EN-313) in Healthy Japanese Volunteers.

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