Chronopharmacology of nebicapone, a new catechol-O-methyltransferase inhibitor.
OBJECTIVE
To investigate the chronopharmacology of nebicapone, a new catechol-O-methyltransferase (COMT) inhibitor currently being developed for use as an adjunct to levodopa/carbidopa or levodopa/benserazide in the treatment of Parkinson's disease.


METHODS
This was a double-blind, randomised, placebo-controlled, parallel-group study. Eighteen Caucasian subjects were randomly assigned to treatment with either nebicapone 100 mg (n = 6), nebicapone 200 mg (n = 6) or placebo (n = 6) at 4-h intervals for 7 days. First dose occurred at 8:00 AM on day 1 and last dose at 8:00 AM on day 8. Blood samples for the determination of plasma drug concentrations of nebicapone and its glucuronidated and methylated metabolites and for the assay of erythrocyte soluble COMT (S-COMT) activity were taken at frequent times following the first and last doses, and before the 8:00 AM and 8:00 PM doses on days 2-7.


RESULTS
Three men and three women in each group participated in the study. Mean +/- SD (range) age of study participants was 23.7 +/- 3.1 (21-28) years in the nebicapone 100 mg group, 22.2 +/- 0.4 (22-23) years in the nebicapone 200 mg group and 24.3 +/- 5.4 (18-32) in the placebo group. A circadian variation in the pre-dose nebicapone and nebicapone-glucuronide plasma concentrations was apparent. Both nebicapone and nebicapone-glucuronide levels were lower before the 8 PM dose in comparison to the 8 AM dose, suggesting that the absorption of nebicapone may follow a circadian variation. S-COMT activity showed no circadian variation in the placebo group. Therefore, the S-COMT activity variation found in nebicapone-treated subjects is considered to be due to changes in plasma concentrations of nebicapone, which is consistent with the fact that the pre-dose S-COMT activity was lower at the time at which nebicapone levels were maximal. Four subjects in the nebicapone 100 mg and placebo groups and six subjects in the nebicapone 200 mg group reported at least one adverse event (AE). All AEs were of mild or moderate intensity. Both nebicapone treatment regimens were subjectively well-tolerated, but a clinically relevant elevation in aspartate transaminase was observed in one subject of each nebicapone group.


CONCLUSIONS
Nebicapone showed chronopharmacology in young Caucasian healthy subjects. The clinical impact of the circadian variation in the nebicapone metabolism and activity in Parkinson's disease patients deserves evaluation as it may have implications for drug prescription by modulating the distribution of the total daily dose along the 24-h scale.
Almeida
Luis
L
Department of Research and Development, Bial - Portela & Ca SA, S. Mamede do Coronado, Portugal.
Loureiro
Ana I
AI
Vaz-da-Silva
Manuel
M
Torrão
Leonel
L
Maia
Joana
J
Fernandes-Lopes
Carlos
C
Falcão
Amílcar
A
Igreja
Bruno
B
Wright
Lyndon
L
Soares-da-Silva
Patricio
P
D000098:Acetophenones / Q000494:pharmacology*; D000293:Adolescent; D000328:Adult; D065098:Catechol O-Methyltransferase Inhibitors; D002940:Circadian Rhythm; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos; D055815:Young Adult
D000098:Acetophenones; D065098:Catechol O-Methyltransferase Inhibitors; D004791:Enzyme Inhibitors; D010919:Placebos; C433466:nebicapone