Roberto Pinto

Opicapone: a short lived and very long acting novel catechol-O-methyltransferase inhibitor following multiple dose administration in healthy subjects.

AIMS The 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. METHODS This 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. RESULTS Opicapone 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. CONCLUSION Despite its short elimination half-life, opicapone markedly and sustainably inhibited erythrocyte S-COMT activity making it suitable for a once daily regimen.

Effect of opicapone on levodopa pharmacokinetics, catechol‐O‐methyltransferase activity and motor fluctuations in patients with Parkinson's disease

Opicapone (OPC) is a novel third generation catechol‐O‐methyltransferase (COMT) inhibitor that enhances levodopa availability. This study investigated the effects of OPC in comparison with placebo on levodopa pharmacokinetics, tolerability and safety, COMT activity and motor response to levodopa in Parkinsons disease (PD) patients with motor fluctuations.

Effect of repeated administration of eslicarbazepine acetate on the pharmacokinetics of simvastatin in healthy subjects.

OBJECTIVE To investigate the effect of eslicarbazepine acetate (ESL) on the pharmacokinetics of simvastatin (SMV), a known CYP3A4 substrate, in healthy subjects. METHODS Single centre, two-way cross-over, randomized, open-label study in 24 healthy volunteers. The volunteers received an oral single-dose of SMV 80mg on two occasions (once administered alone and once after treatment with an oral once-daily dose of 800mg of ESL for 14 days), separated by a wash-out period of 3 weeks or more. The analysis of variance (ANOVA) was used to test for differences between Test (SMV under co-administration with ESL) and Reference (SMV administered alone) treatments for AUC0-∞, AUC0-t and Cmax of SMV and SMV-acid. RESULTS Mean systemic exposure (AUC) measurements for both SMV and SMV-β-hydroxyacid (SMV-acid) were up to 54% lower during ESL use. The Test/Reference geometric mean ratios (GMR) (90% CI) for the AUC0-t of SMV and SMV-acid were 46% (38%; 55%) and 49% (44%; 55%), respectively. Mean peak concentrations (Cmax) of both SMV and SMV-acid were reduced by 60% and 41%, respectively, when SMV was administered with ESL. CONCLUSIONS A significant effect of repeated ESL administration on the pharmacokinetics of SMV and its metabolite SMV-acid was observed. Therefore, dose adjustment of SMV may be required when used concomitantly with ESL, if a clinically significant change in lipids is noted.

Effect of 3 Single-Dose Regimens of Opicapone on Levodopa Pharmacokinetics, Catechol-O-Methyltransferase Activity and Motor Response in Patients With Parkinson Disease.

This study determined the effects of single doses of opicapone (OPC), a novel third‐generation catechol‐O‐methyltransferase (COMT) inhibitor, on levodopa and 3‐O‐methyl‐levodopa (3‐OMD) pharmacokinetics (PK), COMT activity and motor fluctuations in patients with Parkinson disease (PD). Subjects received, in a double‐blind manner, 25, 50, and 100 mg OPC or placebo (PLC) in 4 separate treatment periods. The washout period between doses was at least 10 days. During each period, the OPC/PLC capsules were to be coadministered with the morning dose of 100/25 mg levodopa/carbidopa (LC) or levodopa/benserazide (LB) on day 3. In relation to PLC, levodopa exposure increased 3.7%, 16.4%, and 34.8% following 25, 50, or 100 mg OPC, respectively. Maximum S‐COMT inhibition (Emax) ranged from 67.8% (25 mg OPC) to 100% (100 mg OPC). Peak and extent of S‐COMT inhibition were dose‐dependent. Maximum decrease in the plasma 3‐OMD was observed following administration of 100 mg OPC. Opicapone administered concomitantly with standard‐release 100/25 mg LC or LB improved motor performance. Treatments were generally well tolerated and safe. It was concluded that OPC is a new COMT inhibitor that significantly decreased COMT activity and increased systemic exposure to levodopa in PD patients with motor fluctuations.

Evaluation of opicapone on cardiac repolarization in a thorough QT/QTc study

Opicapone, a novel third‐generation catechol‐O‐methyltransferase inhibitor for use as adjunctive therapy in levodopa‐treated Parkinsons disease patients, was investigated on cardiac repolarization in healthy adult volunteers. This was a single‐center, randomized, double‐blind, placebo‐controlled, open‐label active‐controlled, 4‐period crossover study conducted in 64 subjects. In each period, subjects received a single oral dose of 50 mg opicapone, 800 mg opicapone, placebo, or 400 mg moxifloxacin and 24‐hour 12‐lead Holter monitoring was performed on day ‐1 (baseline) and after each single dose. After a single oral administrations of 50 and 800 mg opicapone, opicapone was the major entity in the circulation, with a median tmax of 1.5–2.0 hours. Opicapone was rapidly eliminated, with an elimination half‐life of 1–2 hours. There was no clinically relevant effect of 50 and 800 mg opicapone versus placebo on cardiac depolarization or repolarization. All upper bounds of the 1‐sided 95% confidence interval (CI) were below 10 milliseconds, confirming that opicapone has no QT‐prolonging effect. Moxifloxacin caused an increase in the QTcI, with a lower bound of the 2‐sided 95% CI always higher than 5 milliseconds, around the tmax of peak concentration, demonstrating assay sensitivity. In conclusion, administration of opicapone at therapeutic (50 mg) and supratherapeutic (800 mg) doses did not induce a clinically significant prolongation of the QTc interval.

Effect of opicapone multiple-dose regimens on levodopa pharmacokinetics, motor response, and erythrocyte-COMT activity in Parkinson's patients co-administered with levodopa/dopa-decarboxylase inhibitor

WCN 2013 No: 1034 Topic: 2 — Movement Disorders Effect of opicapone multiple-dose regimens on levodopa pharmacokinetics, motor response, and erythrocyte-COMT activity in Parkinsons patients co-administered with levodopa/dopa-decarboxylase inhibitor J.J. Ferreira, J.-F. Rocha, A. Falcao, R. Pinto, T. Nunes, P. Soares-da-Silva. Neurological Clinical Research Unit, Instituto de Medicina Molecular, Lisbon, Portugal; Research & Development, BIAL-PortelaC Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal; Dept. of Pharmacology & Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal Background: Opicapone (OPC) was developed to fulfil the need for more potent, safer and longer acting COMT inhibitors. Objectives: Investigate the effect of once-daily 5, 15 and 30 mg OPC, a new COMT inhibitor, on the levodopa pharmacokinetics, in Parkinsons Disease (PD) patients with motor fluctuations treated with standardrelease 100/25 mg levodopa/carbidopa (LC) or levodopa/benserazide (LB). Methods: This was a multicentre, double-blind, randomised, placebocontrolled study in four parallel groups of PD patients treated with LC or LB and with motor fluctuations (“wearing-off” phenomenon). Subjects were sequentially and randomly assigned to be administered, once-daily, during the 21 to 28 day maintenance phase with placebo or 5, 15 and 30 mg OPC. Subjects performed two levodopa tests, one on the morning of the day after admission and another following themaintenance phase. Subjects also kept a diary to record ON/OFF periods. Results: In relation to placebo, levodopa exposure increased 24.73%, 53.93% and 65.61% following 5, 15 or 30 mg OPC. Maximum S-COMT inhibition (Emax) ranged from 52% (5 mg OPC) to 80% (30 mgOPC). The study was not designed to detect any significant differences in motor performance, but the exploratory analysis performed shows improvement in various motor outcomes, including a dose dependent change in absolute OFF time corresponding to a percentage decrease of 0.77%, 4.16%, 29.55% and 32.71% with placebo, 5 mg, 15 mg and 30 mg OPC, respectively. Conclusion: OPC is a promising new COMT inhibitor and deserves further clinical evaluation in larger samples of patients with PD on levodopa treatment with motor fluctuations. doi:10.1016/j.jns.2013.07.390 Abstract — WCN 2013 No: 1038 Topic: 2 — Movement Disorders Efficacy and safety of opicapone, a new COMT-inhibitor, for the treatment of motor fluctuations in Parkinsons Disease patients: BIPARK-II study WCN 2013 No: 1038 Topic: 2 — Movement Disorders Efficacy and safety of opicapone, a new COMT-inhibitor, for the treatment of motor fluctuations in Parkinsons Disease patients: BIPARK-II study A. Lees, J.J. Ferreira, R. Costa, J.-F. Rocha, C. Oliveira, N. Lopes, T. Nunes, P. Soares-da-Silva. National Hospital for Neurology and Neurosurgery, London, UK; Neurological Clinical Research Unit, Instituto de Medicina Molecular, Lisbon, Portugal; Research & Development, BIAL-Portela & Co. S.A., S. Mamede Coronado, Portugal; Dept. of Pharmacology & Therapeutics, Faculty of Medicine, University of Porto,

Atrial Fibrillation as an Ischemic Stroke Clinical and Economic Burden Modifier: A 15-Year Nationwide Study

BACKGROUND Atrial fibrillation (AF) is a major risk factor for ischemic stroke (IS). Patients with AF may undergo preventive therapy. Although the AF impact in the clinical burden of IS has been studied, information is lacking in Southern Europe and there are no studies about the impact in potential years of life lost. Moreover, no nationwide or long-term study analyzed the economic burden of IS stratified by AF. OBJECTIVE To study the impact of AF in the clinical and economic burden of IS. METHODS We conducted a retrospective study using nationwide administrative data for all public hospitalizations in mainland Portugal from 2000 to 2014. We considered IS hospitalizations stratified by the presence of AF as secondary diagnosis. RESULTS Of the total 275,173 IS hospitalizations, 22.6% reported AF. The total number of IS hospitalizations increased from 14,836 in 2000 to 19,561 in 2014 (32% increase), with an increase of 138% in the AF group (from 2,411 to 5,727). In-hospital mortality decreased from 13.6% to 11.5% and was consistently higher in the AF group (17.3% vs. 11.1%). Mean charges were also higher in the AF group (€2297 vs. €2191). Age-adjusted potential years of life lost rate was higher in the group without AF (39.6 vs. 7.5). CONCLUSIONS AF-associated IS hospitalizations more than doubled in the studied 15-year period. Also, AF was responsible for higher in-hospital mortality and hospitalization charges. These facts highlight the need for early detection of AF and preventive treatment to limit IS occurrence, its associated burden, and poorer health outcomes.