Pharmacokinetics of deramciclane and N-desmethylderamciclane after single and repeated oral doses in healthy volunteers.
OBJECTIVE
To study the pharmacokinetics and accumulation of deramciclane and its metabolite N-desmethylderamciclane after 60 mg twice daily doses for 4 weeks.


METHODS
Sixteen healthy male subjects, age range of 20-29 years, participated in this randomized, double-blind, parallel-group, placebo-controlled study. Ten subjects first received a single 60 mg dose of deramciclane followed by 60 mg deramciclane b.i.d. between days 4 and 31. Six subjects received matching placebo in a similar manner. Pharmacokinetics of deramciclane and N-desmethylderamciclane were determined on days 1, 10, 17, 24 and 31. Plasma prolactin concentrations were measured before drug administration and 4 hours after on the same days. Safety was monitored using repeat laboratory determinations and ECG recordings.


RESULTS
The mean (SD) AUC(0-infinity) of deramciclane was 1,251 (385) ng x h/ml after the first dose. The AUC(tau) calculated for the dosing interval was significantly higher at week 1 (p = 0.048) than the AUC(0-infinity) after the first dose but thereafter there was no further accumulation of deramciclane. The mean accumulation indices at weeks 1, 2, 3 and 4 varied between 2.3 and 2.7 with no tendency to increase over time. The mean apparent elimination half-life of deramciclane was 24.9 (3.5) hours after the first dose and 29.3 (9.3) hours after 4-week repeated dosing; this difference was not statistically significant. The accumulation index of N-desmethylderamciclane increased from week 1 to week 2 but remained stable thereafter. The treatment was well tolerated. Plasma prolactin levels were not influenced by deramciclane administration.


CONCLUSIONS
Deramciclane administration, 60 mg twice daily for 4 weeks to healthy male volunteers, is well tolerated, and there is no evidence of continuous accumulation of the drug during maintenance treatment. Deramciclane at a dose of 60 mg b.i.d. does not antagonize dopamine receptors to a significant degree.
Huupponen
R
R
Department of Pharmacology and Clinical Pharmacology, University of Turku, Finland. risto.huupponen@utu.fi
Anttila
M
M
Rouru
J
J
Kanerva
H
H
Miettinen
T
T
Scheinin
M
M
D000328:Adult; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D001892:Camphanes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D011388:Prolactin / Q000097:blood
D014151:Anti-Anxiety Agents; D001892:Camphanes; C406721:N-desmethylderamciclane; D011388:Prolactin; C060555:deramciclane