Pharmacokinetics and safety of deramciclane during multiple oral dosing.
Deramciclane is a new putative non-benzodiazepine-type anxiolytic compound. It is a selective serotonin 5-HT(2A) and 5-HT(2C) receptor antagonist and has also inverse agonist properties. The aim of this study was to reveal the pharmacokinetics and tolerability of deramciclane during repeated oral dosing in healthy male volunteers.


METHODS
A randomized double-blind, placebo-controlled design was used. The study had three consecutive groups that received first a single oral dose of 10, 30 and 60 mg of deramciclane followed by twice a day administration for seven days. The total number of subjects was 28. The pharmacokinetic parameters were calculated for a single dose and after repeated administration. Tolerability was assessed by monitoring safety laboratory variables, electrocardiogram, heart rate, blood pressure and adverse events.


RESULTS
The steady-state was reached during the seven-day administration. The pharmacokinetics of deramciclane was dose-proportional at steady-state at each dose level. Deramciclane accumulated about three-fold during repeated administration. The relative bioavailability of deramciclane increased about 1.4-fold compared to that of a single dose at each dose level. The mean elimination half-life of deramciclane for 10, 30 and 60 mg doses prolonged from 24.3, 20.9 and 22.9 h after a single dose to 30.5, 25.6 and 28.7 h at steady-state, respectively. Only few adverse events were reported, all mild and transient in nature. The most frequently reported adverse drug reactions were tiredness and headache. There were no deramciclane-induced changes in the clinical chemistry or hematology variables, blood pressure, heart rate or in electrocardiogram.


CONCLUSIONS
In conclusion, the pharmacokinetics of deramciclane is linear over the dose range of 10 - 60 mg at steady-state. The slight non-linearity within the dose levels during repeated administration of seven days was regarded as clinically irrelevant. Deramciclane was safe and well tolerated up to doses of 60 mg b.i.d. for seven days.
Kanerva
H
H
Orion Corporation, Orion Pharma, Espoo, Finland.
Kilkku
O
O
Helminen
A
A
Rouru
J
J
Scheinin
M
M
Huupponen
R
R
Klebovich
I
I
Drabant
S
S
Urtti
A
A
D000284:Administration, Oral; D000328:Adult; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D001892:Camphanes / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
D014151:Anti-Anxiety Agents; D001892:Camphanes; D012702:Serotonin Antagonists; C060555:deramciclane