Abstract：
INTRODUCTION:The aim of the study was to clarify the dose response for inhibition of catechol-O-methyltransferase (COMT) by opicapone, a third generation COMT inhibitor, after acute and repeated administration to the cynomolgus monkey with pharmacokinetic evaluation at the higher dose. METHODS:Three cynomolgus monkeys were used in the study. In the first experiment, COMT inhibition was evaluated over 24 h after the first and at 24 h after the last of 14 daily oral administrations of vehicle, 1, 10 and 100 mg/kg opicapone using a crossover design. In the second experiment, the effect of the maximally effective dose, 100 mg/kg, was retested under the same conditions with additional monitoring of plasma opicapone levels to explore the relationship between pharmacokinetics and pharmacodynamics. RESULTS:Opicapone dose-dependently inhibited COMT activity, significantly so at 10 and 100 mg/kg. Maximal inhibition was 13.1%, 76.4% and 93.2% at 1, 10 and 100 mg/kg respectively, and COMT remained significantly inhibited at 24 h after 10 and 100 mg/kg (42.6% and 60.2% respectively). Following repeated administration of opicapone residual COMT inhibition at 24 h was 15-25% greater at all doses. In contrast to its pharmacodynamic effect, opicapone was rapidly absorbed and eliminated, with no accumulation in plasma following repeated administration. CONCLUSION:Opicapone showed sustained and dose-dependent COMT inhibition despite being rapidly eliminated from plasma and with no evidence for accumulation in plasma after 14 days administration. Opicapone fills the unmet need for a compound with sustained COMT inhibition which will improve levodopa bioavailability in patients with Parkinson's disease.
journal_name
Neuropharmacologyjournal_title
Neuropharmacologyauthors
Kitajima T,Mizote S,Bonifácio MJ,Umemura T,Yoneda K,Moser P,Soares-da-Silva P,Tanaka Mdoi
10.1016/j.neuropharm.2018.10.001subject
Has Abstractpub_date
2018-12-01 00:00:00pages
282-288eissn
0028-3908issn
1873-7064pii
S0028-3908(18)30746-9journal_volume
143pub_type
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