Opicapone: a short lived and very long acting novel catechol‐O‐methyltransferase inhibitor following multiple dose administration in healthy subjects

Abstract

AIMSThe 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. METHODSThis 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. RESULTSOpicapone 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. CONCLUSIONDespite its short elimination half-life, opicapone markedly and sustainably inhibited erythrocyte S-COMT activity making it suitable for a once daily regimen. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Currently available catechol-O-methyltransferase (COMT) inhibitors used as adjunctive therapy in levodopa-treated Parkinson's disease patients have clinical limitations. Due to liver toxicity, the use of tolcapone requires liver function monitoring. Entacapone is considered to be safe, but its efficacy is limited and it requires frequent dosing. Opicapone is a novel third generation COMT inhibitor designed to provide high COMT inhibitory potency and avoid cell toxicity. WHAT THIS STUDY ADDS• Based on the observation that the duration of COMT inhibition after opicapone administration is dose-independent and that it reflects an underlying kinetic process that is consistent with the dissociation rate constant of the COMT-opicapone complex, we propose that the sustained COMT inhibition, far beyond the observable point of clearance of circulating drug, is due to the long residence time of the reversible COMT-opicapone complex. The results clearly suggest that opicapone has a unique pharmacodynamic profile adequate for a once daily regimen, which in the treatment of Parkinson's disease patients could represent an advantage over entacapone and tolcapone.

Structure-based drug design of catechol-O-methyltransferase inhibitors for CNS disorders

“…In addition, it presents favourable pharmacodynamics with L-dopa, resulting in stable and sustained plasma L-dopa concentrations over prolonged periods [43]. In fact, opicapone is currently under phase III clinical trials for the therapy of Parkinson's disease [44,45]. Studies involving human subjects have confirmed that opicapone is a very long acting inhibitor and a once daily regimen may be Structure-based design of COMT inhibitors effective [44,45].…”

“…In fact, opicapone is currently under phase III clinical trials for the therapy of Parkinson's disease [44,45]. Studies involving human subjects have confirmed that opicapone is a very long acting inhibitor and a once daily regimen may be Structure-based design of COMT inhibitors effective [44,45]. Computational analyses indicate that the long acting inhibition primarily depends on the catalytic rate constant (Kcat) of the inhibitor's O-methylation rather than the rate constant of dissociation (Koff) of the enzymeinhibitor complex [46].…”

Spotlight on opicapone as an adjunct to levodopa in Parkinson’s disease: design, development and potential place in therapy

“…Rocha et al28 hypothesized that the long-lasting effect of OPC might be related to its binding to the complex of COMT–SAHcy, thus blocking the exchange of SAM to SAHcy and therefore hindering the O -methylation of another OPC molecule.…”

“…In nonclinical studies, the following five metabolites of OPC have been detected: BIA 9-1100 and BIA 9-1101 are inactive methylated metabolites, BIA 9-1103 is an inactive sulfated metabolite, BIA 9-1106 is an inactive glucuronide metabolite and BIA 9-1079 is an active COMT-inhibitor metabolite 27,28. OPC is mainly metabolized by sulfation to BIA 9-1103.…”

Rational drug discovery design approaches for treating Parkinson’s disease

“…Opicapone [76] (structure not shown) is a third-generation long-acting COMT inhibitor that markedly increases systemic and central levodopa bioavailability. A Phase III study with opicapone in fluctuating parkinsonian patients has been concluded in 2012 [77].…”