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Movement disorders
Published in Henry J. Woodford, Essential Geriatrics, 2022
COMTi act by blocking one of the degradation pathways of levodopa (to 3-o-methyldopa) (seeFigure 9.8). Tolcapone has both central and peripheral actions but due to cases of hepatoxicity, its use is limited.39 It is only tried under expert supervision for people unresponsive to other COMTi and with regular monitoring of liver blood tests. Entacapone does not cross the blood-brain barrier. It has a half-life of just one hour and is taken with each dose of levodopa. It increases the half-life of levodopa without increasing the maximum concentration and so, should be less likely to worsen dyskinesias. The benefit is in the order of an additional 30 minutes ‘on' time with each levodopa dose.40 It can be helpful for people who are experiencing motor fluctuations.41 A 15–30% reduction in levodopa dose is recommended at the initiation of entacapone therapy. It has not been associated with hepatic toxicity. Patients should be warned that an orange discolouration of their urine could occur. It occasionally causes diarrhoea and may precipitate psychosis. Preparations containing levodopa, a decarboxylase inhibitor and entacapone in combination are available. Opicapone is a once-daily COMTi that appears similarly effective to entacapone in the treatment of PD when added to levodopa (mean age 64).42 Dyskinesias occurred in 4% of people given a placebo, 8% on entacapone and 16% on opicapone. The adverse effect profile is similar and the levodopa dose should also be reduced at commencement of opicapone. COMTi may be considered for the management of motor fluctuations in advanced PD.7
Redefining the strategy for the use of COMT inhibitors in Parkinson’s disease: the role of opicapone
Published in Expert Review of Neurotherapeutics, 2021
Peter Jenner, José-Francisco Rocha, Joaquim J Ferreira, Olivier Rascol, Patrício Soares-da-Silva
The persistent enzyme inhibition produced by opicapone translates into functional activity that can be seen both invitro and invivo experimental models. In liver and kidney homogenates from rats treated orally with opicapone, tolcapone or entacapone, opicapone produced a more marked and more sustained inhibition of COMT than the other drugs [58,59]. The effects on levodopa (in conjunction with a DDC inhibitor) metabolism also reflects the long-lasting inhibition of COMT produced by opicapone. Oral administration of opicapone with levodopa to rats resulted in a sustained increase in brain levodopa levels that was evident 24 hours after drug administration. Similar results were seen in the cynomolgus monkey, where administration of adjunct opicapone to levodopa/benserazide increased levodopa systemic exposure by 2-fold without changing Cmax values [60,61] and reduced both 3-OMD exposure and Cmax values by up to 7-fold [60,61]. These changes were accompanied by an up to ~85% reduction in erythrocyte COMT activity [60,61] and translated into an improvement in motor function in MPTP treated parkinsonian primates [61]. (Figures 1 and 2)[62,63]
Cost-effectiveness of opicapone and entacapone in reducing OFF-time in Parkinson’s disease patients treated with levodopa/carbidopa
Published in Journal of Medical Economics, 2021
Ryan N. Hansen, Kangho Suh, Michael Serbin, Chuck Yonan, Sean D. Sullivan
Opicapone is a novel, long-acting, peripherally selective, once-daily, oral COMT inhibitor9 that was approved by the FDA in 2020 as adjunctive treatment to levodopa/carbidopa (LD/CD) in PD patients experiencing OFF episodes. Approval of opicapone was based on results from two randomized, double-blind, placebo-controlled, pivotal Phase 3 studies, BIPARK-1 (NCT01568073)10 and BIPARK-2 (NCT01227655)11. In BIPARK-1, patients with end-of-dose motor fluctuations (mean OFF-time of approximately 6 h daily) were randomized to one of three doses of opicapone (5 mg, 25 mg, or 50 mg), placebo, or entacapone (200 mg with every LD/CD dose). The primary endpoint assessed change from baseline in absolute OFF-time, and opicapone 50 mg was shown to be clinically and statistically superior to placebo in decreasing OFF-time (–116.8 min daily vs −56.0 min daily, p = 0.0015), and non-inferior to entacapone (–96.3 min, p = 0.0051)10. Similar results for opicapone 50 mg vs placebo in BIPARK-2 were observed, although the latter trial did not include an active comparator11. Based on the BIPARK-1 and BIPARK-2 trials, as well as a pharmacokinetic study12, the MDS EBM review concluded that opicapone was efficacious and clinically useful for the treatment of motor fluctuations with no significant safety concerns8.
The launch of opicapone for Parkinson’s disease: negatives versus positives
Published in Expert Opinion on Drug Safety, 2018
Ana Castro Caldas, Tiago Teodoro, Joaquim J Ferreira
Opicapone is a new, long-acting, peripherally selective, once-daily, COMT inhibitor that significantly prolongs and enhances the bioavailability of levodopa. Across all clinical studies, both doses of opicapone (25 and 50 mg once daily) consistently reduced OFF time and increased ON time without troublesome dyskinesia. These benefits were sustained over 1 year in two open-label extension studies. It was approved in 2016 by the European Medicines Agency as adjunctive therapy to levodopa in adult patients with PD and end-of-dose motor fluctuations. It is already marketed in the United Kingdom, Germany, Italy, and Spain. Compared to entacapone, OPC 50 mg seems to present a higher magnitude of effect in OFF-time reduction and performed better for both clinician’s and patient’s global impression scales suggesting a potential higher clinical benefit. In BIPARK I, the higher frequency of reported dyskinesia with opicapone compared to entacapone also goes in line with a more potent dopaminergic effect.