Pharmacokinetic Dynamic Relationships
Opicapone: a short lived and very long acting novel catechol-O-methyltransferase inhibitor following multiple dose administration in healthy subjects
Article first published online: 21 OCT 2013
© 2013 BIAL – Portela and Cª S.A. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 76, Issue 5, pages 763–775, November 2013
How to Cite
Rocha, J. F., Almeida, L., Falcão, A., Palma, P. N., Loureiro, A. I., Pinto, R., Bonifácio, M. J., Wright, L. C., Nunes, T. and Soares-da-Silva, P. (2013), Opicapone: a short lived and very long acting novel catechol-O-methyltransferase inhibitor following multiple dose administration in healthy subjects. British Journal of Clinical Pharmacology, 76: 763–775. doi: 10.1111/bcp.12081
- Issue published online: 21 OCT 2013
- Article first published online: 21 OCT 2013
- Accepted manuscript online: 21 JAN 2013 07:36AM EST
- Manuscript Accepted: 22 DEC 2012
- Manuscript Received: 28 AUG 2012
- BIAL – Portela & Cª, S.A
- COMT inhibition;
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.
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.
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.
Despite its short elimination half-life, opicapone markedly and sustainably inhibited erythrocyte S-COMT activity making it suitable for a once daily regimen.