A single- and multiple-dose study to investigate the pharmacokinetics and pharmacodynamics of opicapone, a novel COMT inhibitor, in rat. (October 2017)

• Record Type: Journal Article
• Authors: Gonçalves, Daniela; Alves, Gilberto; Fortuna, Ana; Bonifácio, Maria João; Soares-da-Silva, Patrício; Falcão, Amílcar
• Is Part Of: Neuropharmacology. Volume 125(2017)
• Page Start: 146
• Page End: 155
• Publication Date: 2017-10
• Subjects: Opicapone -- Catechol-O-Methyltransferase inhibitor -- Rat -- Pharmacodynamics -- Pharmacokinetics; AADCI aromatic l-amino acid decarboxylase inhibitor -- AUC area under the drug concentration-time curve -- AUCextrap area under the drug concentration-time curve extrapolated from the time of the last measurable concentration to infinity -- AUCτ area under the drug concentration-time curve within a dosing interval -- AUC0-inf area under the drug concentration-time curve from time zero to infinity -- AUC0-t area under the drug concentration-time curve from time zero to the time of the last measurable concentration -- AUC0–24h area under the drug concentration-time curve from time zero to 24 h -- AUEC area under the effect–time curve -- AUEC0–24h area under the effect–time curve from time zero to 24 h -- AUEC0–72h area under the effect–time curve from time zero to 72 h -- CL/F apparent clearance -- Clast last measurable concentration -- Cmax maximum concentration -- COMT catechol-O-methyltransferase -- Emax maximum inhibition of catechol-O-methyltransferase activity -- HPLC high performance liquid chromatography -- HPMC hydroxypropyl methylcellulose -- k kinetic recovery constant -- ktis apparent tissue elimination rate constant -- kel apparent plasma elimination rate constant -- IC50 half maximal inhibitory concentration -- LLOQ lower limit of quantification -- MRT mean residence time -- MB-COMT membrane-bound catechol-O-methyltransferase isoform -- Rac observed accumulation ratio -- R0 theoretical accumulation ratio -- SAM S-adenosyl-l-methionine -- S-COMT soluble catechol-O-methyltransferase isoform -- SEM standard error of the mean -- t1/2tis tissue elimination half-life -- t1/2el plasma elimination half-life -- tlast time of the last measurable concentration -- tEmax time to achieve the maximum inhibition of catechol-O-methyltransferase activity -- tmax time to reach the maximum peak concentration -- τ dosing interval; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2017.07.019
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Opicapone is a novel catechol- O -methyltransferase (COMT) inhibitor that emerged to fulfil the need of a safer and more efficacious COMT inhibitor. The present study was carried out in order to assess and compare the pharmacokinetics and pharmacodynamics (COMT inhibition) of opicapone after single and multiple oral administrations (30 mg/kg) to Wistar rats. For this purpose, at predefined time points up to 72 h post-dosing, blood, liver and kidneys were collected and, then, the concentrations of opicapone and its active metabolite (BIA 9–1079) were determined in plasma and in liver and kidney tissues, as well as the erythrocyte, liver and kidney COMT activity. No systemic, renal or hepatic accumulation of opicapone was observed following repeated administration. Furthermore, the tissue-systemic exposure relationships to opicapone suggested a low drug exposure in the liver and kidneys. After single-dosing, COMT inhibition profiles were reasonably comparable in all the studied matrices; although similar results were found after multiple-dosing, a higher degree of inhibition was observed, indicating a continuous peripheral COMT inhibition when opicapone is administered once-daily. Despite having a short elimination half-life (≤2.94 h), opicapone showed a strong and long-lasting COMT inhibition in both studies, since more than 50% of the COMT activity was still inhibited at 24 h post-dosing. Graphical abstract: Highlights: Opicapone was rapidly absorbed and eliminated after oral administration to rats. No systemic, renal or hepatic accumulation of opicapone occurred after multiple-doses. A low exposure of the liver and kidney to opicapone was observed. A strong, sustained and long-lasting COMT inhibition was shown in all matrices.