Pharmacokinetics of Opicapone and Its Metabolites in Healthy White and Chinese Subjects.

Opicapone (OPC) is a third-generation catechol-O-methyltransferase inhibitor developed to treat Parkinson disease and motor fluctuations. This open-label, single-center, phase 1 study aimed to evaluate the pharmacokinetics (PK) of OPC and its metabolites when administered as single and multiple doses in healthy White and Chinese subjects. The study enrolled a total of 30 White and Chinese healthy subjects, equally balanced among groups. The first dose of OPC was administered orally as a single dose of 50 mg on day 1, followed by a 10-day once-daily treatment from day 5 to day 14. Plasma concentrations of OPC and its metabolites were measured at 0 to 72 and 0 to 144 hours after dosing for single dose and multiple dose, respectively. Moreover, urine concentrations of OPC and its metabolite were measured 0 to 24 hours after dosing. PK parameters were derived from noncompartmental analysis. Geometric mean ratios and 90% confidence intervals for the main PK parameters were conducted to evaluate the ethnic difference between White and Chinese subjects. The plasma and urine exposure of OPC and its metabolites in Chinese subjects were similar to those in White subjects. These results indicated that ethnicity had no significant impact on PK of OPC between White and Chinese subjects.

Metabolism and elimination of the catechol-o-methyltransferase inhibitor tolcapone in the horse.

The metabolism of the masking agent tolcapone in the horse has been investigated. This substance was found to have undergone various chemical transformations that produced a large variety of phase I metabolites, as well as glucuronide and sulfate conjugation. Confirmation of the presence of tolcapone and the 3-O-methylated metabolite in the blood samples collected up to 240 minutes and in urine obtained up to 24 hours, was successfully conducted using both gas chromatography- and liquid chromatography-tandem mass spectrometry techniques. The 3-O-methyl tolcapone is the better marker to use in a screening method because, in comparison to tolcapone, we have found that this substance offers superior chromatographic performance that should potentially give a lower limit of detection.

A single- and multiple-dose study to investigate the pharmacokinetics and pharmacodynamics of opicapone, a novel COMT inhibitor, in rat.

Opicapone is a novel catechol-O-methyltransferase (COMT) inhibitor that emerged to fulfil the need of a safer and more efficacious COMT inhibitor. The present study was carried out in order to assess and compare the pharmacokinetics and pharmacodynamics (COMT inhibition) of opicapone after single and multiple oral administrations (30 mg/kg) to Wistar rats. For this purpose, at predefined time points up to 72 h post-dosing, blood, liver and kidneys were collected and, then, the concentrations of opicapone and its active metabolite (BIA 9-1079) were determined in plasma and in liver and kidney tissues, as well as the erythrocyte, liver and kidney COMT activity. No systemic, renal or hepatic accumulation of opicapone was observed following repeated administration. Furthermore, the tissue-systemic exposure relationships to opicapone suggested a low drug exposure in the liver and kidneys. After single-dosing, COMT inhibition profiles were reasonably comparable in all the studied matrices; although similar results were found after multiple-dosing, a higher degree of inhibition was observed, indicating a continuous peripheral COMT inhibition when opicapone is administered once-daily. Despite having a short elimination half-life (≤2.94 h), opicapone showed a strong and long-lasting COMT inhibition in both studies, since more than 50% of the COMT activity was still inhibited at 24 h post-dosing.

Pharmacokinetics of opicapone, a third-generation COMT inhibitor, after single and multiple oral administration: A comparative study in the rat.

Opicapone is a novel potent, reversible and purely peripheral catechol-O-methyltransferase inhibitor that has been developed to be used as an adjunct to levodopa/aromatic L-amino acid decarboxylase inhibitor therapy for Parkinson's disease. Thus, this study aimed to compare the plasma pharmacokinetics of opicapone and its active metabolite (BIA 9-1079) after the administration of single and multiple oral doses to rats. Wistar rats (n=8 per group) were orally treated with single (30, 60 or 90mg/kg) or multiple (30mg/kg once-daily for seven consecutive days) oral doses of opicapone. Blood samples were collected up to 24h post-dosing through a cannula introduced in the tail vein of rats. After quantifying opicapone and BIA 9-1079 in plasma, a non-compartmental pharmacokinetic analysis was performed. Opicapone was quickly absorbed (time to reach the maximum plasma concentration≤2h) in both dosage regimens and the extent of systemic exposure to opicapone increased approximately in a dose-proportional manner after single-dosing within the studied dose range (30-90mg/kg). Opicapone and BIA 9-1079 showed a relatively short plasma elimination half-life (1.58-4.50h) and a small systemic accumulation after multiple-dosing. Hence, no pharmacokinetic concerns are expected when opicapone is administered with a once-daily dosing regimen.

Effect of opicapone multiple-dose regimens on levodopa pharmacokinetics.

AIMS: To compare the levodopa/carbidopa (LC) and levodopa/benserazide (LB) pharmacokinetic profiles following repeated doses of opicapone (OPC) administered apart from levodopa. METHODS: Two randomized, double blind, sex-balanced, placebo-controlled studies in four groups of 12 or 18 healthy subjects each. In each group, enrolled subjects received a once-daily morning (5, 15 and 30 mg) or evening (5, 15 and 50 mg) administration of OPC or placebo for up to 28 days. On the morning of Day 11, 12 h after the OPC or placebo evening dose, or the morning of Day 21, 1 h after the OPC or placebo dose, a single dose of immediate-release 100/25 mg LC was administered. Similarly, on Day 18 morning, 12 h after the OPC or placebo evening dose, or Day 28 morning, 1 h after the OPC or placebo dose, a single dose of immediate-release 100/25 mg LB was administered. RESULTS: All OPC treatments, in relation to the placebo group, presented a higher extent of exposure (AUC) to levodopa following either LC or LB doses. A relevant but not dose-dependent increase in the levodopa AUC occurred with all OPC dose groups in relation to placebo. All active treatments significantly inhibited both peak (Emax ) and extent (AUEC) of the catechol-O-methyltransferase activity in relation to placebo. The tolerability profile was favourable. CONCLUSION: Opicapone, as once-daily oral evening regimen and/or 1 h apart from levodopa therapy, increases the bioavailability of levodopa associated with its pronounced, long-lasting and sustained catechol-O-methyltransferase inhibition. The tolerability profile was favourable and similar between OPC and placebo.

Development of a physiologically based pharmacokinetic/pharmacodynamic model to identify mechanisms contributing to entacapone low bioavailability.

Entacapone is an inhibitor of catechol-O-methyltransferase (COMT) and is being used to extend the therapeutic effect of levodopa in patients with advanced and fluctuating Parkinson's disease. Entacapone has low and variable oral bioavailability and the underlying mechanism(s) for this behavior have not been studied. To explain such behavior and to characterize the dynamic changes in the metabolism of entacapone, a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model was developed integrating in silico, in vitro and in vivo pharmacokinetic data. The model was developed and verified in healthy volunteers and subsequently expanded to predict the pharmacokinetic parameters of entacapone phosphate, a prodrug of entacapone, and to assess the impact of hepatic impairment on the pharmacokinetics of entacapone. Low and inter-individual variability in bioavailability could be attributed to the extensive first-pass metabolism by UGTs in the liver and, to a lesser extent, the small intestine. The predictive performance of this model was acceptable with predicted Cmax , AUC and PD parameters lying within 20% of the observed data. The model indicates that the low bioavailability could be attributed to the extensive first-pass effect of entacapone.

Fewer fluctuations, higher maximum concentration and better motor response of levodopa with catechol-O-methyltransferase inhibition.

Catechol-O-methyltransferase inhibitor addition to levodopa/carbidopa formulations improves motor symptoms and reduces levodopa fluctuations in patients with Parkinson's disease. Objectives were to investigate the effects of entacapone and tolcapone on plasma behaviour of levodopa, its metabolite 3-O-methyldopa and on motor impairment. 22 patients orally received levodopa/carbidopa first, then levodopa/carbidopa/entacapone and finally levodopa/carbidopa plus tolcapone within a 4.5 h interval twice. Maximum concentration, time to maximum level and bioavailability of levodopa did not differ between all conditions each with 200 mg levodopa application as a whole. Catechol-O-methyltransferase inhibition caused less fluctuations and higher baseline levels of levodopa after the first intake and less 3-O-methyldopa appearance. The maximum levodopa concentrations were higher after the second levodopa intake, particularly with catechol-O-methyltransferase inhibition. The motor response to levodopa was better with catechol-O-methyltransferase inhibition than without, tolcapone was superior to entacapone. More continuous levodopa brain delivery and lower 3-O-methyldopa bioavailability caused a better motor response during catechol-O-methyltransferase inhibition.