OBJECTIVE: The present study aimed at evaluating the effect of opicapone, a 
third generation nitrocatechol catechol-O-methyltransferase (COMT) inhibitor, on 
the systemic and central bioavailability of 3,4-dihydroxy-l-phenylalanine 
(levodopa) and related metabolites in the cynomolgus monkey.
METHODS: Four monkeys, implanted with guiding cannulas for microdialysis probes, 
in the substantia nigra, dorsal striatum and prefrontal cortex, were randomized 
in two groups that received, in a crossover design, vehicle or 100 mg/kg 
opicapone for 14 days. Twenty-three hours after last administration of vehicle 
or opicapone, animals were challenged with levodopa/benserazide (12/3 mg/kg). 
Extracellular dialysate and blood samples were collected over 360 min (at 30 min 
intervals) for the assays of catecholamine and COMT activity.
RESULTS: Opicapone increased levodopa systemic exposure by 2-fold not changing 
Cmax values and reduced both 3-O-methyldopa (3-OMD) exposure and Cmax values by 
5-fold. These changes were accompanied by ∼76-84% reduction in erythrocyte COMT 
activity. In dorsal striatum and substantia nigra, opicapone increased levodopa 
exposure by 1.7- and 1.4-fold, respectively, reducing 3-OMD exposure by 5- and 
7-fold respectively. DOPAC exposure was increased by 4-fold in the substantia 
nigra. In the prefrontal cortex, opicapone increased levodopa exposure and 
reduced 3-OMD levels by 2.3- and 2.4-fold, respectively.
CONCLUSIONS: Opicapone behaved as long-acting COMT inhibitor that markedly 
increased systemic and central levodopa bioavailability. Opicapone is a strong 
candidate to fill the unmet need for COMT inhibitors that lead to more sustained 
levodopa levels in Parkinson's disease patients.