title: Evaluation of opicapone on cardiac repolarization in a thorough QT/QTc study.
abstract: Opicapone, a novel third-generation catechol-O-methyltransferase inhibitor for use as adjunctive therapy in levodopa-treated Parkinson's 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.
authors.affiliation: Dept. Research & Development, BIAL-Portela & Cª-S.A., 4745-457 S. Mamede do Coronado, Portugal.|Dept. Pharmacology & Therapeutics, Faculty of Medicine, University Porto, Porto, Portugal.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pinto
authors.affiliation: Biotrial, Rennes, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: l'Hostis
authors.affiliation: Biotrial, Rennes, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Patat
authors.affiliation: Biotrial, Rennes, France.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Homery
authors.affiliation: Dept. Pharmacology, Faculty of Pharmacy, University Coimbra, Coimbra, Portugal.
authors.forename: Amílcar
authors.initials: A
authors.lastname: Falcão
authors.affiliation: Dept. Research & Development, BIAL-Portela & Cª-S.A., 4745-457 S. Mamede do Coronado, Portugal.
authors.forename: Teresa
authors.initials: T
authors.lastname: Nunes
authors.affiliation: Dept. Research & Development, BIAL-Portela & Cª-S.A., 4745-457 S. Mamede do Coronado, Portugal.
authors.forename: José-Francisco
authors.initials: JF
authors.lastname: Rocha
authors.affiliation: Dept. Research & Development, BIAL-Portela & Cª-S.A., 4745-457 S. Mamede do Coronado, Portugal.|Dept. Pharmacology & Therapeutics, Faculty of Medicine, University Porto, Porto, Portugal.|MedInUP-Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal.
authors.forename: Patrício
authors.initials: P
authors.lastname: Soares-da-Silva
mesh_terms: D000200:Action Potentials; D000293:Adolescent; D000328:Adult; D065098:Catechol O-Methyltransferase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D004311:Double-Blind Method; D015716:Electrocardiography, Ambulatory; D005260:Female; D024841:Fluoroquinolones / Q000009:adverse effects; D005602:France; D064368:Healthy Volunteers; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D010069:Oxadiazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D018570:Risk Assessment; D013997:Time Factors; D055815:Young Adult
chemical_list: D065098:Catechol O-Methyltransferase Inhibitors; D024841:Fluoroquinolones; D010069:Oxadiazoles; D000077266:Moxifloxacin; C549349:opicapone
keywords: COMT inhibitors; QT; QTc; cardiac repolarization; opicapone