title: Opicapone: a short lived and very long acting novel catechol-O-methyltransferase inhibitor following multiple dose administration in healthy subjects.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  Despite its short elimination half-life, opicapone markedly and sustainably inhibited erythrocyte S-COMT activity making it suitable for a once daily regimen.
authors: Department of Research & Development, Mamede do Coronado, Portugal.
authors: José Francisco
authors: JF
authors: Rocha
authors: Luis
authors: L
authors: Almeida
authors: Amílcar
authors: A
authors: Falcão
authors: P Nuno
authors: PN
authors: Palma
authors: Ana I
authors: AI
authors: Loureiro
authors: Roberto
authors: R
authors: Pinto
authors: Maria João
authors: MJ
authors: Bonifácio
authors: Lyndon C
authors: LC
authors: Wright
authors: Teresa
authors: T
authors: Nunes
authors: Patrício
authors: P
authors: Soares-da-Silva
mesh_terms: D000328:Adult; D000978:Antiparkinson Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D065098:Catechol O-Methyltransferase Inhibitors; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D010069:Oxadiazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000978:Antiparkinson Agents; D065098:Catechol O-Methyltransferase Inhibitors; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; C549349:opicapone
keywords: COMT inhibition; catechol-O-methyltransferase; opicapone; pharmacodynamics; pharmacokinetics