What is opicapone?

Opicapone: A Third-Generation COMT Inhibitor for Parkinson's Disease

Opicapone is a once-daily, peripherally-selective catechol-O-methyltransferase (COMT) inhibitor used as adjunctive therapy to levodopa/DOPA decarboxylase inhibitor combinations in Parkinson's disease patients experiencing end-of-dose motor fluctuations. 1

Mechanism of Action

Opicapone works by:

• Selectively and reversibly inhibiting COMT, an enzyme that metabolizes levodopa
• Preventing the conversion of levodopa to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD)
• Increasing levodopa bioavailability in the brain
• Extending the duration of levodopa's therapeutic effect
• Reducing "OFF" periods in Parkinson's disease patients 1

Clinical Benefits

When added to levodopa/carbidopa therapy, opicapone:

• Increases peak levodopa concentration (Cmax) by 43-44%
• Increases overall levodopa exposure (AUC) by 62-94%
• Reduces daily "OFF" time by approximately 60 minutes compared to placebo
• Maintains efficacy during long-term treatment (up to 1 year)
• Does not increase troublesome dyskinesias 2

Dosing and Administration

• Standard dose: 50 mg once daily at bedtime
• Should be taken at least 1 hour before or after levodopa/carbidopa administration
• Dose adjustment for moderate hepatic impairment (Child-Pugh B): 25 mg once daily
• Avoid use in patients with severe hepatic impairment (Child-Pugh C)
• No dose adjustment required for mild renal impairment
• Avoid use in patients with end-stage renal disease 1

Pharmacokinetics

• Absorption: Reaches peak plasma concentration in approximately 2 hours
• Food effect: High-fat meals decrease absorption (62% decrease in Cmax, 31% decrease in AUC)
• Metabolism: Primarily through sulfation, with minor contribution from renal elimination
• COMT inhibition: Maximal inhibition of 84%, maintained >65% over 24 hours
• Duration of effect: COMT inhibition persists >35% even 5 days after the last dose 1

Safety Profile

Opicapone is generally well-tolerated with:

• Most common adverse events: dyskinesia, constipation, and insomnia
• Low incidence of serious adverse events (3.5%, similar to placebo at 4.3%)
• No evidence of hepatic toxicity (unlike tolcapone)
• Low incidence of gastrointestinal disorders like nausea and diarrhea (<2%)
• No significant changes in laboratory parameters, vital signs, or ECG readings 3

Advantages Over Other COMT Inhibitors

Compared to earlier COMT inhibitors (entacapone and tolcapone), opicapone offers:

• Once-daily dosing (versus multiple daily doses for entacapone)
• No risk of liver toxicity (a concern with tolcapone)
• Longer duration of action
• Simplified treatment regimen
• Better tolerability profile 4

Clinical Considerations

• Opicapone appears particularly beneficial in patients with less advanced disease and mild motor fluctuations
• Earlier introduction in the therapeutic management of motor fluctuations may provide better benefit-risk ratio
• May also help with fluctuation-related pain in Parkinson's disease, though research is ongoing 5, 6

Monitoring

• Regular monitoring of levodopa-related side effects is recommended, particularly dyskinesia
• Dose adjustment of levodopa may be necessary after initiating opicapone
• No specific laboratory monitoring required (unlike tolcapone)

Opicapone represents an important advancement in the management of Parkinson's disease motor fluctuations, offering a convenient once-daily dosing regimen with a favorable safety profile compared to earlier COMT inhibitors.