Effect of opicapone on levodopa pharmacokinetics, catechol-O-methyltransferase activity and motor fluctuations in patients with Parkinson's disease

Background and purposeOpicapone (OPC) is a novel third generation catechol-O-methyltransferase (COMT) inhibitor that enhances levodopa availability. This study investigated the effects of OPC in comparison with placebo on levodopa pharmacokinetics, tolerability and safety, COMT activity and motor response to levodopa in Parkinson's disease (PD) patients with motor fluctuations. MethodsThis was a randomized, multicentre, double-blind and placebo-controlled study in four parallel groups of PD patients treated with standard-release 100/25mg levodopa/carbidopa or levodopa/benserazide and with motor fluctuations (wearing-OFF phenomenon). Subjects were sequentially assigned to be administered, once-daily, up to 28days (maintenance phase), placebo (n=10) or 5 (n=10), 15 (n=10) and 30mg (n=10) OPC. Two levodopa tests were performed, one at baseline and another following the maintenance phase. Subjects kept a diary to record motor fluctuations (ON/OFF periods) throughout the study. ResultsIn relation to placebo, levodopa exposure (AUC(0-6)) increased 24.7%, 53.9% and 65.6% following 5, 15 and 30mg OPC, respectively. Maximum COMT inhibition (E-max) ranged from 52% (5mg OPC) to 80% (30mg OPC). The study was not designed to detect any significant differences in motor performance, but the exploratory analysis performed shows improvement in various motor outcomes, including a dose-dependent change in absolute OFF time corresponding to a percentage decrease of 4.16% (P>0.05), 29.55% (P>0.05) and 32.71% (P<0.05) with 5, 15 and 30mg OPC, respectively. Treatments were generally well tolerated and safe. ConclusionsOPC is a promising new COMT inhibitor that significantly decreased COMT activity, increased systemic exposure to levodopa and improved motor response.