ODM-104 and Optimized Carbidopa Dose Show Beneficial Effect on Levodopa PK in Healthy Subjects (P6.028)

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 biovailability may be reduced. When AADC is inhibited, levodopa is metabolized increasingly by COMT. Simultaneous COMT-inhibition improves levodopa bioavailability. Design/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 7 th 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 (AUC 0–24h ) 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 AUC 0–24h and also the minimum concentrations (C min,tau ) of levodopa without significantly increasing its maximum concentrations (C max,tau ). When compared to standard carbidopa/levodopa, ODM-104 100 mg + carbidopa 65 mg + MR levodopa treatment decreased levodopa fluctuation (PTF tau ) 62% (p min,tau 212% and AUC 0–24h 105% (p max,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 AUC 0–24h and triples the C min,tau of levodopa without significantly increasing its C max,tau . Disclosure: Dr. Tuunainen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Orion Oyj. Dr. Ellmen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Orion Oyj. Dr. Vahteristo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Orion Oyj. Dr. Vahteristo holds stock and/or stock options in Orion Oyj. Dr. Holopainen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Orion Oyj. Dr. Strugala has nothing to disclose.