Objective: To evaluate the plasma pharmacokinetics (PK) of orally administered modified release (MR) levodopa in combination with the aromatic L-amino acid decarboxylase inhibitor carbidopa and a novel catechol-O-methyl transferase (COMT) inhibitor, ODM-104, compared to the standard carbidopa/levodopa/entacapone combination.

Background: In Parkinson’s disease, stable levodopa concentrations in plasma predict improved treatment responses with reduced motor fluctuations. MR formulations of levodopa help to achieve stable drug concentrations, but levodopa biovailability may be compromised and is often unpredictable. COMT inhibition improves levodopa bioavailability. This study evaluated the effect of ODM-104, a novel inhibitor of COMT, on the PK properties of MR levodopa administered in combination with an optimized dosage of carbidopa in healthy volunteer subjects.

Methods: An open, randomized, 3-period cross-over PK study was conducted with 15 healthy subjects. Carbidopa and COMT inhibitors were administered q.i.d. for 6 days and on the 7th day, levodopa 100 mg q.i.d. was added to the treatments. 25 and 65 mg of carbidopa in combination with ODM-104 100 mg and MR levodopa were investigated and compared to Stalevo® with 200 mg of entacapone and 25 mg of carbidopa. All statistical models are adjusted for age, weight and gender.

Results: With ODM-104 + carbidopa 65 mg + MR levodopa, levodopa fluctuation (PTF (C _max,tau-C _min,tau/C _av,tau x 100 and C _max/C_min ratio) was decreased (p < 0.05 and p < 0.0001), and minimum concentrations (C _{min, tau}) and exposure (AUC _{0-24 h}) were increased (p < 0.01 and p = 0.01) compared to Stalevo®. Minimum levodopa concentrations were increased by 36 % and AUC by 15%, with a trend to reduced maximum concentrations (C _{max, tau}) by 10 % (p = 0.33).With ODM-104 + carbidopa 25 mg, fluctuation was also decreased (p = 0.1 and p < 0.001) compared to Stalevo®, without differences in levodopa C _{min, tau} or AUC _0-24h.

Conclusions: With a novel COMT inhibitor, ODM-104, and MR levodopa, levodopa fluctuation in plasma was reduced without any loss of its bioavailability. Increasing the carbidopa dosage in the combination increased levodopa bioavailability and minimum concentrations without increasing the peak concentrations.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-novel-comt-inhibitor-odm-104-and-optimized-carbidopa-in-combination-with-modified-release-levodopa-reduce-levodopa-fluctuation-and-increase-minimum-concentrations-in-healthy-subjects-when-compare/