Objective: To evaluate the effect of repeated OPC treatments, COMT inhibition versus plasma opicapone level, dose response of COMT inhibition, and systematic and central bioavailability of L-dopa in cynomolgus monkeys.

Background: L-dopa continues to be the most effective agent for the symptomatic treatment of Parkinson’s disease. Even fast metabolic elimination is inhibited by decarboxylase inhibitors, levodopa metabolism is predominantly shifted to COMT. Opicapone (OPC) is a high binding affinity and long-acting third generation nitrocatechol COMT inhibitor. The long-acting COMT inhibition was not based on pharmacokinetics improvement but considered to be depend tight-binding inhibition characteristics.

Methods: Adult cynomolgus monkeys (Macaca Fascicularis), 3-6 years old and weighing 2.4 – 4.5 kg were used. Subjects were dosed for 14 days with OPC (1-100 mg/kg/10ml/day, po) with vehicle, 0.2% hydroxypropylmethylcellulose. COMT activity was determined in erythrocytes. Plasma opicapone concentration was quantified with by LC/MS. Levodopa was quantified in deproteinized plasma by HPLC-ED.

Results: OPC was rapidly absorbed and eliminated, and not accumulated. In contrast, OPC continuously decreased COMT activity, >90% inhibition at maximum and ~60% at 24 h on day 1, and further inhibited COMT after repeated treatment. OPC increased L-dopa exposure by 2-fold in plasma and >1.4-fold in the brain, without affecting Cmax. OPC showed sustained COMT inhibition, and markedly increased systemic and central L-dopa bioavailability.

Conclusions: Opicapone (OPC) was rapidly absorbed and eliminated after oral administration, but showed sustained COMT inhibition, and markedly increased systemic and central L-dopa bioavailability. The increase of L-dopa bioavailability was accompanied with a shift in L-dopa tmax (time to Cmax) to a later time, but without significantly affecting L-dopa Cmax levels. The data suggests that OPC fulfils the unmet need for sustained COMT inhibition which will improve levodopa bioavailability in patients with Parkinson’s disease.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/novel-comt-inhibitor-opicapone-shows-sustained-inhibition-and-improved-l-dopa-availability-in-monkeys/