Session Information
Date: Saturday, October 6, 2018
Session Title: Parkinson’s Disease: Clinical Trials, Pharmacology And Treatment
Session Time: 1:45pm-3:15pm
Location: Hall 3FG
Objective: ODM-104 is a novel non-nitrocatechol catechol-O-methyltransferase (COMT) inhibitor that is undergoing clinical evaluation for Parkinson’s disease (PD). This study investigated the pharmacodynamic effects of ODM-104 in preclinical assays.
Background: COMT inhibition is important part of the triple combination used in the treatment of PD. Bioavailability of levodopa in the brain markedly improves when peripheral metabolism is inhibited. When amino acid decarboxylase is inhibited, levodopa is metabolized increasingly via COMT and efficacious COMT inhibition is needed to improve levodopa’s efficacy.
Methods: COMT inhibition by ODM-104 was studied using recombinant human COMT isoforms. Levodopa levels in plasma and COMT inhibition in peripheral tissues was studied after the triple combination (levodopa+carbidopa+ODM-104/entacapone/vehicle) in rats. Rotational behavior by the triple combination was investigated in different paradigms in 6-hydroxydopamine lesioned PD rats. Dopamine (DA) turnover after ODM-104 was measured in rat cerebrospinal fluid (CSF) and in caudate nucleus and serial CSF samples in dogs.
Results: ODM-104 potently and selectively inhibited soluble and membrane-bound COMT enzymes. COMT inhibition in the peripheral tissues was more efficient and longer lasting with ODM-104 than with entacapone. Levodopa area-under-curve (AUC)0-4 in plasma was higher and the PD rats rotated markedly more after ODM-104 than after entacapone. DA turnover (DA/DOPAC [3,4-dihydroxyphenylacetic acid] -ratio) was increased and COMT-dependent homovanillic acid was reduced in the CSF and caudate nucleus.
Conclusions: ODM-104 potently and long-lastingly inhibited COMT activity in peripheral tissues and improved bioavailability and antiparkinsonian efficacy of levodopa in the rat brain more than entacapone did. Although ODM-104 is mainly peripheral COMT inhibitor, clinically relevant doses may improve dopamine turnover in the brain. ODM-104 shows superior preclinical pharmacodynamic effects to entacapone.
To cite this abstract in AMA style:
S. Janhunen, J. Venäläinen, J. Kaskinoro, L. Saloranta, J. Tuunainen. A novel non-nitrocatechol COMT inhibitor ODM-104 shows superior pharmacodynamic effects to entacapone [abstract]. Mov Disord. 2018; 33 (suppl 2). https://www.mdsabstracts.org/abstract/a-novel-non-nitrocatechol-comt-inhibitor-odm-104-shows-superior-pharmacodynamic-effects-to-entacapone/. Accessed June 14, 2025.« Back to 2018 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-non-nitrocatechol-comt-inhibitor-odm-104-shows-superior-pharmacodynamic-effects-to-entacapone/