Pharmacokinetics, Pharmacodynamics and Tolerability of Opicapone, a Novel Catechol-O-Methyltransferase Inhibitor, in Healthy Subjects

Abstract

Opicapone was well-tolerated and presented dose-proportional kinetics. Opicapone demonstrated marked and sustained inhibition of erythrocyte soluble COMT activity. Based on the observation that the half-life of COMT inhibition is independent of the dose and that it reflects an underlying kinetic process that is consistent with the k(off) value of the COMT-opicapone complex, we propose that the sustained COMT inhibition, far beyond the observable point of clearance of circulating drug, is due to the long residence time of the reversible complex formed between COMT and opicapone. Globally, these promising results provide a basis for further clinical development of opicapone.

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“…After 24 h of intake, OPC exerted COMT inhibitory effect ranging from 26.1% (10 mg) to 76.5% (800 mg). At 72 h post-dose, OPC still had COMT inhibitory effect: 5.9% (10 mg OPC) to 54.6% (800 mg) 27. Systemic exposure to OPC was significantly lower after a high-fat, high-calorie meal compared to after fasting, implying that OPC should be taken before meals.…”

“…LD was given concomitantly and maximum LD concentration was detected between 1.5 h and 3.5 h. The maximum COMT inhibition was dose dependent and ranged between 36.1% (10 mg OPC) and 100% (200 mg–1,200 mg OPC). The inhibitory effect reached its peak between 0.7 h and 6.2 h post-dose 27. After 24 h of intake, OPC exerted COMT inhibitory effect ranging from 26.1% (10 mg) to 76.5% (800 mg).…”

“…Almeida et al27 found that after a single oral administration of various doses (10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 400 mg, 800 mg and 1,200 mg) of OPC to healthy subjects, the terminal half-life ranged between 0.8 h (for 50 mg) and 3.2 h (for 1,200 mg). LD was given concomitantly and maximum LD concentration was detected between 1.5 h and 3.5 h. The maximum COMT inhibition was dose dependent and ranged between 36.1% (10 mg OPC) and 100% (200 mg–1,200 mg OPC).…”

“…In nonclinical studies, the following five metabolites of OPC have been detected: BIA 9-1100 and BIA 9-1101 are inactive methylated metabolites, BIA 9-1103 is an inactive sulfated metabolite, BIA 9-1106 is an inactive glucuronide metabolite and BIA 9-1079 is an active COMT-inhibitor metabolite 27,28. OPC is mainly metabolized by sulfation to BIA 9-1103.…”

“…OPC is mainly metabolized by sulfation to BIA 9-1103. Reduction to BIA 9-1079 and glucuronidation to BIA 9-1106 are alternate metabolic routes 27,28. A total of 70% of orally administered radiolabeled 14 C-OPC was eliminated by feces in human beings,23 whereas 12% of the drug was excreted by urine.…”