Objective: To study the dose effects of a novel catechol-O-methyl transferase (COMT) inhibitor ODM-104 and the aromatic L-amino acid decarboxylase (AADC) inhibitor carbidopa on levodopa pharmacokinetics (PK) at 3 modified release (MR) levodopa strengths and to compare with a standard carbidopa/levodopa immediate release (IR) formulation.

Background: In Parkinson’s disease, stable levodopa concentration in plasma predicts improved treatment response with reduced motor fluctuations. MR formulations of levodopa help to achieve stable concentrations but levodopa bioavailability may be reduced. When AADC is inhibited, levodopa is metabolized increasingly by COMT. Simultaneous COMT-inhibition improves levodopa bioavailability.

Methods: An open, randomized, repeated dose PK study with 56 healthy males. The study consisted of 4 parallel groups with 4-treatmet crossover design. The effect of two carbidopa and ODM-104 doses on MR levodopa PK was investigated. AADC and COMT inhibitors were administered q.i.d for 7 days and on the 7th day MR levodopa 50, 100 or 150 mg was added into the treatment.

Results: At each levodopa dose level, 65 mg of carbidopa significantly increased the exposure (AUC0-24h) of levodopa when compared to standard (1:4 carbidopa to levodopa ratio) dose. Addition of ODM-104 (50 or 100 mg) dose dependently significantly further increased the AUC0-24h and also the minimum concentrations (Cmin,tau) of levodopa without significantly increasing its maximum concentrations (Cmax,tau). When compared to standard carbidopa/levodopa, ODM-104 100 mg + carbidopa 65 mg + MR levodopa treatment decreased levodopa fluctuation (PTFtau) 62% (p < 0.0001) and increased Cmin,tau 212% and AUC0-24h 105% (p < 0.0001). Levodopa Cmax,tau was increased 24% (p=0.5).

Conclusions: Increased carbidopa dose and ODM-104 have a role in increasing the exposure and decreasing the fluctuation of MR levodopa. When compared to standard carbidopa/levodopa, ODM-104 100 mg + carbidopa 65 mg + MR levodopa treatment doubles the AUC0-24h and triples the Cmin,tau of levodopa without significantly increasing its Cmax,tau. The abstract will be presented in AAN annual meeting in Los Angeles on April 27, 2018.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/odm-104-and-optimized-carbidopa-dose-show-beneficial-effect-on-levodopa-pk-in-healthy-subjects/