Effect of 3 Single‐Dose Regimens of Opicapone on Levodopa Pharmacokinetics, Catechol‐O‐Methyltransferase Activity and Motor Response in Patients With Parkinson Disease

Abstract

This study determined the effects of single doses of opicapone (OPC), a novel third-generation catechol-O-methyltransferase (COMT) inhibitor, on levodopa and 3-O-methyl-levodopa (3-OMD) pharmacokinetics (PK), COMT activity and motor fluctuations in patients with Parkinson disease (PD). Subjects received, in a double-blind manner, 25, 50, and 100 mg OPC or placebo (PLC) in 4 separate treatment periods. The washout period between doses was at least 10 days. During each period, the OPC/PLC capsules were to be coadministered with the morning dose of 100/25 mg levodopa/carbidopa (LC) or levodopa/benserazide (LB) on day 3. In relation to PLC, levodopa exposure increased 3.7%, 16.4%, and 34.8% following 25, 50, or 100 mg OPC, respectively. Maximum S-COMT inhibition (Emax ) ranged from 67.8% (25 mg OPC) to 100% (100 mg OPC). Peak and extent of S-COMT inhibition were dose-dependent. Maximum decrease in the plasma 3-OMD was observed following administration of 100 mg OPC. Opicapone administered concomitantly with standard-release 100/25 mg LC or LB improved motor performance. Treatments were generally well tolerated and safe. It was concluded that OPC is a new COMT inhibitor that significantly decreased COMT activity and increased systemic exposure to levodopa in PD patients with motor fluctuations.

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

“…A marked decrease was observed in peak 3-OMD levels and also in the extent of exposure with 100 mg OPC. All active treatments inhibited the extent and rate of COMT activity in a dose-dependent, albeit disproportional, manner 37. Motor responses were also measured.…”

“…In a phase II study, patients diagnosed with idiopathic PD, who had at least 1.5 h long OFF state in the waking day and a modified Hoehn–Yahr stage of <5 in the OFF state, received 25 mg, 50 mg, and 100 mg OPC or PLC once daily in addition to their previous 100/25 mg LD and CD or BZ therapy 37. The maximum plasma concentration of LD dose dependently increased after OPC intake compared to PLC.…”

Opicapone for the treatment of Parkinson’s disease: an update

“…Two phase II and two phase III studies provide information on clinical efficacy of OPC (Table 1) [21]. No serious adverse events were detected in the two studies mentioned above [21,34].…”

Recent advances in treating Parkinson’s disease

“…To prolong and enhance the action of L-Dopa, the new reversible MAO B-inhibitor safinamide 27– 32 —with the claim that this compound also influences glutamatergic transmission—and the long-lasting COMT inhibitor opicapone 33– 35 have been approved (both at present in Europe). An extended-release (24-hour long-acting) formulation of amantadine has been recently reported to markedly reduce the severity and extent of L-Dopa-induced dyskinesia and also to reduce off-time 36, 37 .…”