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.

AIMSThe aim of this study was to assess the tolerability, pharmacokinetics and inhibitory effect on erythrocyte soluble catechol-O-methyltransferase (S-COMT) activity following repeated doses of opicapone. METHODSThis randomized, placebo-controlled, double-blind study enrolled healthy male subjects who received either once daily placebo or opicapone 5, 10, 20 or 30 mg for 8 days. RESULTSOpicapone was well tolerated. Its systemic exposure increased in an approximately dose-proportional manner with an apparent terminal half-life of 1.0 to 1.4 h. Sulphation was the main metabolic pathway. Opicapone metabolites recovered in urine accounted for less than 3% of the amount of opicapone administered suggesting that bile is likely the main route of excretion. Maximum S-COMT inhibition (Emax) ranged from 69.9% to 98.0% following the last dose of opicapone. The opicapone-induced S-COMT inhibition showed a half-life in excess of 100 h, which was dose-independent and much longer than plasma drug exposure. Such a half-life translates into a putative underlying rate constant that is comparable with the estimated dissociation rate constant of the COMT-opicapone complex. CONCLUSIONDespite its short elimination half-life, opicapone markedly and sustainably inhibited erythrocyte S-COMT activity making it suitable for a once daily regimen. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Currently available catechol-O-methyltransferase (COMT) inhibitors used as adjunctive therapy in levodopa-treated Parkinson's disease patients have clinical limitations. Due to liver toxicity, the use of tolcapone requires liver function monitoring. Entacapone is considered to be safe, but its efficacy is limited and it requires frequent dosing. Opicapone is a novel third generation COMT inhibitor designed to provide high COMT inhibitory potency and avoid cell toxicity. WHAT THIS STUDY ADDS• Based on the observation that the duration of COMT inhibition after opicapone administration is dose-independent and that it reflects an underlying kinetic process that is consistent with the dissociation rate constant 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 COMT-opicapone complex. The results clearly suggest that opicapone has a unique pharmacodynamic profile adequate for a once daily regimen, which in the treatment of Parkinson's disease patients could represent an advantage over entacapone and tolcapone.

SUMMARYPurpose: To evaluate the pharmacokinetics and tolerability of once-daily eslicarbazepine acetate (ESL) and twicedaily oxcarbazepine (OXC) and their metabolites in cerebrospinal fluid (CSF) and plasma following repeated oral administration. Methods: Single-center, open-label, randomized, parallelgroup study in healthy volunteers. Volunteers in ESL group (n = 7) received 600 mg on days 1-3 and 1,200 mg on days 4-9, once daily. Volunteers in the OXC group (n = 7) received 300 mg on days 1-3 and 600 mg on days 4-9, twice daily. Plasma and CSF sampling was performed following the last dose. Key Findings: Eslicarbazepine was the major drug entity in plasma and CSF, accounting for, respectively, 93.84% and 91.96% of total exposure in the ESL group and 78.06% and 76.42% in the OXC group. The extent of exposure to drug entities R-licarbazepine and oxcarbazepine was approximately four-fold higher with OXC as compared with ESL. There was relatively little fluctuation from peak-to-trough (ratio) in the CSF for both eslicarbazepine (ESL = 1.5; OXC = 1.2) and R-licarbazepine (ESL = 1.2; OXC = 1.2). In contrast, oxcarbazepine showed larger differences between peak and trough (ESL = 3.1; OXC = 6.4). A total of 84 and 24 treatment-emergent adverse events (TEAEs) were reported with OXC and ESL, respectively. Significance: In comparison to OXC, administration of ESL resulted in more eslicarbazepine, less R-licarbazepine, and less oxcarbazepine in plasma and CSF, which may correlate with the tolerability profile reported with ESL. The smaller peak-to-trough fluctuation of eslicarbazepine in CSF (a measure of sustained delivery to the brain) than in plasma supports once-daily dosing of ESL.

SummaryObjective: We assessed the efficacy and safety of once-daily eslicarbazepine acetate in comparison with twice-daily (BID) controlled-release carbamazepine (carbamazepine-CR) monotherapy in newly diagnosed focal epilepsy patients. Methods: This randomized, double-blind, noninferiority trial (NCT01162460) utilized a stepwise design with 3 dose levels. Patients who remained seizure-free for the 26-week evaluation period (level A: eslicarbazepine acetate 800 mg/carbamazepine-CR 200 mg BID) entered a 6-month maintenance period. If a seizure occurred during the evaluation period, patients were titrated to the next target level (level B: eslicarbazepine acetate 1200 mg/carbamazepine-CR 400 mg BID, level C: eslicarbazepine acetate 1600 mg/carbamazepine-CR 600 mg BID) and the evaluation period began again. The primary endpoint was the proportion of seizure-free patients for 6 months after stabilization in the per protocol set. The predefined noninferiority criteria were À12% absolute and À20% relative difference between treatment groups. Results: Eight hundred fifteen patients were randomly assigned; 785 (388 in the eslicarbazepine acetate group and 397 in the carbamazepine-CR group) were included in the per protocol set, and 813 (401 in the eslicarbazepine acetate group and 412 in the carbamazepine-CR group) were included in the full analysis set for the primary analysis. Overall, 71.1% of eslicarbazepine acetate-treated patients and 75.6% of carbamazepine-CR-treated patients were seizure-free for ≥6 months at the last evaluated dose (average risk difference = À4.28%, 95% confidence interval [CI] = À10.30 to 1.74; relative risk difference = À5.87%, 95% CI = À13.50 to 2.44) in the per protocol set. Rates of treatment-emergent adverse events were similar between groups for patients in the safety set. Noninferiority was also demonstrated in the full analysis set, as 70.8% of patients with eslicarbazepine acetate and 74.0% with carbamazepine-CR were seizure-free at the last evaluated dose (average risk difference = À3.07, 95% CI = À9.04 to

ESL (800 and 1200mg QD) was effective and well tolerated as adjunctive therapy for adults with refractory POS.