BACKGROUND AND OBJECTIVES: Opicapone is a novel catechol-O-methyltransferase 
(COMT) inhibitor. The purpose of this study was to evaluate the tolerability, 
pharmacokinetics (including the effect of food) and pharmacodynamics (effect on 
COMT activity) following single oral doses of opicapone in young healthy male 
volunteers.
METHODS: Single rising oral doses of opicapone (10, 25, 50, 100, 200, 400, 800 
and 1,200 mg) were administered to eight groups of eight subjects per group (two 
subjects randomized to placebo and six subjects to opicapone), under a 
double-blind, randomized, placebo-controlled design. In an additional group of 
12 subjects, a 50 mg single dose of opicapone was administered on two occasions, 
once having fasted overnight and once with a high-fat high-calorie meal.
RESULTS: Opicapone was well tolerated at all doses tested. The extent of 
systemic exposure (area under the plasma concentration-time curve and maximum 
plasma concentration) to opicapone and metabolites increased in an approximately 
dose-proportional manner and showed a decrease following concomitant ingestion 
of a high-fat high-calorie meal. The apparent terminal elimination half-life of 
opicapone was 0.8-3.2 h. Sulphation appeared to be the main metabolic pathway 
for opicapone, and both opicapone and the main sulphated metabolite are likely 
excreted by the biliary route. Maximum COMT inhibition by opicapone was dose 
dependent, ranged from 36.1% (10 mg) to 100% (200 mg and above), and reached 
statistical significance at all doses tested. The long duration of COMT 
inhibition by opicapone, however, tended to be independent from the dose taken. 
The observed half-life of opicapone-induced COMT inhibition in human 
erythrocytes was 61.6 h (standard deviation [SD] = 37.6 h), which reflects an 
underlying dissociative process with a kinetic rate constant of 3.1 × 10(-6) 
s(-1) (SD = 1.9 × 10(-6) s(-1)). Such a process compares well to the estimated 
dissociation rate constant (k(off)) of the COMT-opicapone molecular complex 
(k(off) = 1.9 × 10(-6) s(-1)).
CONCLUSIONS: Opicapone was well-tolerated and presented dose-proportional 
kinetics. Opicapone demonstrated marked and sustained inhibition of erythrocyte 
soluble COMT activity. Based on the observation that the half-life of COMT 
inhibition is independent of the dose and that it reflects an underlying kinetic 
process that is consistent with the k(off) value of the COMT-opicapone complex, 
we propose that the sustained COMT inhibition, far beyond the observable point 
of clearance of circulating drug, is due to the long residence time of the 
reversible complex formed between COMT and opicapone. Globally, these promising 
results provide a basis for further clinical development of opicapone.