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 (E_max) 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.

DOI: 10.1111/bcp.12081

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