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Lyndon C. Wright - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics disposition and metabolism of 14c Nebicapone in humans
Drug Metabolism Letters, 2010Co-Authors: Lyndon C. Wright, Luis Almeida, Ana I. Loureiro, Joana Maia, Patricio SoaresdasilvaAbstract:Objective: This study investigated the absorption, distribution, metabolism and excretion (ADME) of Nebicapone [BIA 3-202; 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone], a reversible catechol-O-methyltransferase (COMT) inhibitor, in 4 healthy male subjects. Methods; This was a single center, open, non-placebo-controlled, single-group, and a single 200 mg dose study of [14C]-Nebicapone (2.5 MBq). Blood, urine and faeces were collected up to 264 hours post-dose. Results: Collectively more than 22 metabolites were identified in plasma, urine and faeces, with 3-ONebicapone- glucuronide (BIA 3-476) identified as the major metabolite. Plasma concentration-time profiles of [14C]- Nebicapone demonstrated Tmax (h) 1.25±0.65, t1/2 (h) 134.55±25.67, Cmax (ng-eq/g) 19647.02±4930.20, AUC0-t (h.ng-eq/g) 161735.51±9224.66, AUC0-∞ (h.ng-eq/g) 199603.30±16854.08, and for whole blood Tmax 1.00±0.41, t1/2 32.98±22.82, AUC0-t 35539.23±13664.87, AUC0-∞ 36970.64±14559.17. Plasma pharmacokinetics of Nebicapone demonstrated Tmax (h) 1.00±0.41, t1/2 (h) 2.34±0.51; Cmax (ng-eq/g) 12650.00±2898.85, AUC0-t (h.ng-eq/g) 18719.96±734.18, AUC0-∞ (h.ngeq/ g) 18392.12±753.81; BIA 3-476 demonstrated Tmax 1.25±0.50, t1/2 3.47±0.68; Cmax 15250±2563.20, AUC0-t 53810.61 ±7358.81, AUC0-∞ 54541.21±7135.70; 3-O-methyl-Nebicapone (BIA 3-270) demonstrated Tmax 21.01±6.01 , t1/2 103.43± 6.01; Cmax 286.25±20.48, AUC0-t 27641.89±4569.99, AUC0-∞ 36968.12±4294.42. Conclusions: Nebicapone and BIA 3- 476 accounted for most early phase circulating Nebicapone-derived moieties, have limited circulating cell association, peak concentrations shortly after dosing, and short body residence. In longer terminal half-life phases low concentrations of BIA 3-270 predominate. While about 70% of the dose was eliminated in the urine as BIA 3-476, < 1% of the dose was excreted as unchanged Nebicapone. Faecal excretion accounted for 17.3% administered dose. On average, the total recovery of 88.6% of the radioactivity suggested no worrisome retention of drug derived material following a single 200 mg administration of Nebicapone to healthy volunteers. The treatment was very well tolerated with no reported adverse events.
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Chronopharmacology of Nebicapone, a new catechol-O-methyltransferase inhibitor
Current medical research and opinion, 2010Co-Authors: Luís Pereira De Almeida, Manuel Vaz-da-silva, Amílcar Falcão, Ana I. Loureiro, Carlos Fernandes-lopes, Lyndon C. Wright, Joana Maia, Leonel Torrao, Bruno Igreja, Patrício Soares-da-silvaAbstract:Objective: To investigate the chronopharmacology of Nebicapone, a new catechol-O-methyltransferase (COMT) inhibitor currently being developed for use as an adjunct to levodopa/carbidopa or levodopa/benserazide in the treatment of Parkinson’s disease. Methods: This was a double-blind, randomised, placebo-controlled, parallel-group study. Eighteen Caucasian subjects were randomly assigned to treatment with either Nebicapone 100 mg (n ¼ 6), Nebicapone 200 mg (n ¼ 6) or placebo (n ¼ 6) at 4-h intervals for 7 days. First dose occurred at 8:00 AM on day 1 and last dose at 8:00 AM on day 8. Blood samples for the determination of plasma drug concentrations of Nebicapone and its glucuronidated and methylated metabolites and for the assay of erythrocyte soluble COMT (S-COMT) activity were taken at frequent times following the first and last doses, and before the 8:00 AM and 8:00 PM doses on days 2–7. Results:
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species differences in pharmacokinetic and pharmacodynamic properties of Nebicapone
Biochemical Pharmacology, 2009Co-Authors: Maria João Bonifácio, Ana I. Loureiro, Lyndon C. Wright, Leonel Torrao, Carlos Fernandeslopes, Maria Joao Pinho, Patricio SoaresdasilvaAbstract:The present study was designed to characterize pharmacodynamic and pharmacokinetic properties of Nebicapone in rats and mice. Upon oral administration of Nebicapone the extent of mouse liver catechol-O-methyltransferase (COMT) inhibition is half that in the rat. Nebicapone was rapidly absorbed reaching plasma C(max) within 30min and being completely eliminated by 8h. Nebicapone was metabolized mainly by glucuronidation and methylation in both species, but rat had an extra major metabolite, resulting from sulphation. Administration of Nebicapone by the intraperitoneal route significantly increased compound AUC in the rat while in the mouse a significant increase in AUC of metabolites was observed. These results show that Nebicapone exhibited marked species differences in bioavailability and metabolic profile. Evaluation of COMT activity in rat and mice liver homogenates revealed that both had similar methylation efficiencies (K(cat) values, respectively 7.3 and 6.4min(-1)), but rat had twice active enzyme units as the mouse (molar equivalency respectively 150 and 83). Furthermore, Nebicapone inhibited rat liver COMT with a lower K(i) than mouse liver COMT (respectively 0.2nM vs. 1.2nM). In conclusion, the results from the present study show that mice and rats respond differently to COMT inhibition by Nebicapone. The more pronounced inhibitory effects of Nebicapone in the rat may be related to an enhanced oral availability and less pronounced metabolism of Nebicapone in this specie, but also concerned with the predominant expression of S-COMT over MB-COMT, the latter of which is less sensitive to inhibition by Nebicapone than the former.
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pharmacokinetic pharmacodynamic interaction between Nebicapone and controlled release levodopa benserazide a single center phase i double blind randomized placebo controlled four way crossover study in healthy subjects
Clinical Therapeutics, 2009Co-Authors: Teresa G. Nunes, Amílcar Falcão, Ana I. Loureiro, Leonel Torrao, Carlos Fernandeslopes, Rita Machado, Jose Francisco Rocha, R Costa, Manuel Vazdasilva, Lyndon C. WrightAbstract:Abstract Background: Nebicapone is a reversible catechol-O-methyltransferase (COMT) inhibitor. Coadministration of a COMT inhibitor with levodopa and a dopa-decarboxylase inhibitor (carbidopa or benserazide) increases levodopa exposure and its therapeutic effect. Objectives: The primary objective of this study was to investigate the effect of Nebicapone (50, 100, and 200 mg), compared with placebo, on levodopa pharmacokinetics when coadministered with a single dose of controlled-release levodopa 100 mg/benserazide 25 mg. The secondary objectives were to investigate the effect of Nebicapone on the erythrocyte-soluble COMT (S-COMT) activity and on the plasma levels of the levodopa 3- O -methylated metabolite (3- O -methyldopa [3-OMD]). Nebicapone's tolerability was also assessed. Methods: This was a single-center, Phase I, doubleblind, randomized, placebo-controlled, 4-way crossover study conducted in healthy adult volunteers. Each of the 4 single-dose treatment periods was separated by a washout period of ≥5 days. During the different treatment periods, subjects received a single dose of controlled-release levodopa 100 mg/benserazide 25 mg concomitantly with Nebicapone 50, 100, and 200 mg or placebo. Plasma concentrations of Nebicapone, levodopa, and 3-OMD were determined by HPLC. Blood samples (7 mL) for determination of plasma concentrations of levodopa, 3-OMD, and 2258 Nebicapone, as well as for the assay of S-COMT activity, were collected in potassium EDTA test tubes at the following times: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose. S-COMT activity was assessed as the amount of metanephrine formed by the action of S-COMT on an epinephrine substrate. Spontaneously reported clinical adverse events (AEs) were recorded throughout the study. Results: Sixteen subjects (8 females, 8 males; mean [SD] age, 26.13 [6.29] years; weight, 69.4 [12.4] kg; body mass index, 24.0 [3.0] kg/m 2 ) completed the 4 treatment periods and had data available for pharmacokinetic and pharmacodynamic analyses. Compared with placebo, levodopa C max increased 25%, 30%, and 34%, and AUC increased 14%, 37%, and 42% after administration of Nebicapone 50, 100, and 200 mg, respectively. After administration of Nebicapone 50, 100, and 200 mg, 3-OMD C max decreased 44%, 57%, and 58%, and 3-OMD AUC 0–∞ decreased 33%, 37%, and 45%, respectively, compared with placebo. Extent of exposure to levodopa, as assessed by using AUC 0−t , increased with all doses of Nebicapone in relationship to placebo, but the difference did not reach statistical significance. This may be related to a relatively high inter-subject variability: %CVs ranged from 48.0% with Nebicapone 100 mg to 66.8% with placebo. Maximum S-COMT inhibition by Nebicapone occurred at ~1.5 hours postdose and ranged from 57% with Nebicapone 50 mg to 74% with Nebicapone 200 mg. There was an inverse correlation between plasma concentrations of Nebicapone and S-COMT activity; T max of Nebicapone plasma concentrations and time to occurrence of the maximum inhibition of S-COMT activity appeared to correlate. Nineteen AEs were reported; 8 were assessed by the investigator as possibly related to treatment. All AEs were mild in severity. There were no serious AEs or discontinuations due to AEs. No abnormalities in liver enzyme levels were found. Conclusions: When administered concomitantly with a single dose of controlled-release levodopa 100 mg/benserazide 25 mg, single doses of Nebicapone 50, 100, and 200 mg were well tolerated in these healthy adult volunteers, and dose dependently inhibited S-COMT activity and reduced 3-OMD formation compared with placebo. However, there was no significant difference in levodopa bioavailability.
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poster abstract 7 pharmacokinetic pharmacodynamic interaction between Nebicapone bia 3 202 and controlled release levodopa benserazide madopar hbs 125
Neurotherapeutics, 2008Co-Authors: Luís Pereira De Almeida, Teresa G. Nunes, Leonel Torrao, Rita Machado, Jose Francisco Rocha, R Costa, Manuel Vazdasilva, Carlos Lopes, A I Loureiro, Lyndon C. WrightAbstract:Background and Objective Nebicapone (formerly known as BIA 3-202) is a new catechol-O-methyltransferase (COMT) inhibitor in development as a levodopa-sparing agent to be used in levodopa-treated Parkinson disease patients. The objective of this study was to investigate the effect of single oral doses of Nebicapone (50 mg, 100 mg and 200 mg) on the levodopa and 3-O-methyldopa (3-OMD) systemic exposure and erythrocyte soluble COMT (S-COMT) activity when coadministered with a single-dose of controlled-release levodopa/benserazide 100/25 mg (Madopar HBS 125). Methods Double-blind, randomized, placebo-controlled, four-way crossover study in 16 healthy subjects, with a washout of 5 or more days between periods. Results Taking placebo as reference, levodopa AUC0-t geometric mean ratios (GMR) and 90% confidence intervals (90%CI) were 1.14 (0.83;1.65), 1.37 (0.91;1.80), and 1.42 (0.97;1.92) for Nebicapone 50 mg, 100 mg and 200 mg, respectively. Regarding 3-OMD, AUC0-t GMR and 90%CI were 0.67 (0.53;0.80), 0.63 (0.51;0.77), and 0.55 (0.49;0.75), respectively. Maximum S-COMT inhibition occurred at 1.5 h after the dose and ranged from 57% with Nebicapone 50 mg to 74% with Nebicapone 200 mg. There was an inverse correlation between plasma concentrations of Nebicapone and S-COMT activity, and Nebicapone tmax correlated well with tEmax of S-COMT inhibition. Treatments were well tolerated. Conclusions Single doses of 50 mg, 100 mg, and 200 mg of the novel COMT inhibitor Nebicapone dose-dependently and significantly inhibited S-COMT activity, increased the bioavailability of levodopa, and reduced the formation of 3-OMD, when administered concomitantly with controlled-release levodopa/benserazide 100/25 mg (Madopar HBS 125). Supported by BIAL-Portela & Ca SA.
Teresa G. Nunes - One of the best experts on this subject based on the ideXlab platform.
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a double blind randomized placebo and active controlled study of Nebicapone for the treatment of motor fluctuations in parkinson s disease
CNS Neuroscience & Therapeutics, 2010Co-Authors: Joaquim J Ferreira, Luis Almeida, Teresa G. Nunes, Patricio Soaresdasilva, Jose Francisco Rocha, Olivier Rascol, Werner Poewe, Cristina SampaioAbstract:To determine the efficacy, safety and tolerability of Nebicapone, a new catechol-O-methyltransferase inhibitor for the treatment of motor fluctuations in Parkinson's disease (PD), we conducted a multicenter, randomized, 8-week double-blind, placebo- and active-controlled, parallel-group study comparing Nebicapone 50 mg, 100 mg, or 150 mg, entacapone 200 mg (active control) or placebo administered concomitantly with levodopa/carbidopa or levodopa/benserazide. Two hundred and fifty-two PD patients with motor fluctuations treated with levodopa/carbidopa or levodopa/benserazide (4-8 daily doses) were enrolled and 250 patients were eligible for intention-to-treat (ITT) analysis on the basis of having at least one efficacy assessment. The primary endpoint was 8-week change from baseline in absolute "Off" time duration noted in self-scoring diaries. At 8 weeks of treatment the mean daily "Off" time decreased significantly compared to placebo for Nebicapone 150 mg (-106 min; 95%CI: -192; -21) and entacapone 200 mg (-81 min; 95%CI: -142; -19). The decrease in "Off" time with Nebicapone 50 mg or 100 mg did not reach statistical significance. Treatment-emergent adverse events were reported by 32% to 49% of patients in any treatment group, with no observed dose relationship in the Nebicapone groups. Clinically relevant elevations in aspartate transaminase (AST) and/or alanine transaminase (ALT) were observed in 4 of 46 patients with the Nebicapone 150 mg dose. The results of this study show that Nebicapone 150 mg is efficacious for the treatment of motor fluctuations in PD patients. However, the risk of increasing liver transaminases and its clinically relevance deserves further evaluation.
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pharmacokinetic pharmacodynamic interaction between Nebicapone and controlled release levodopa benserazide a single center phase i double blind randomized placebo controlled four way crossover study in healthy subjects
Clinical Therapeutics, 2009Co-Authors: Teresa G. Nunes, Amílcar Falcão, Ana I. Loureiro, Leonel Torrao, Carlos Fernandeslopes, Rita Machado, Jose Francisco Rocha, R Costa, Manuel Vazdasilva, Lyndon C. WrightAbstract:Abstract Background: Nebicapone is a reversible catechol-O-methyltransferase (COMT) inhibitor. Coadministration of a COMT inhibitor with levodopa and a dopa-decarboxylase inhibitor (carbidopa or benserazide) increases levodopa exposure and its therapeutic effect. Objectives: The primary objective of this study was to investigate the effect of Nebicapone (50, 100, and 200 mg), compared with placebo, on levodopa pharmacokinetics when coadministered with a single dose of controlled-release levodopa 100 mg/benserazide 25 mg. The secondary objectives were to investigate the effect of Nebicapone on the erythrocyte-soluble COMT (S-COMT) activity and on the plasma levels of the levodopa 3- O -methylated metabolite (3- O -methyldopa [3-OMD]). Nebicapone's tolerability was also assessed. Methods: This was a single-center, Phase I, doubleblind, randomized, placebo-controlled, 4-way crossover study conducted in healthy adult volunteers. Each of the 4 single-dose treatment periods was separated by a washout period of ≥5 days. During the different treatment periods, subjects received a single dose of controlled-release levodopa 100 mg/benserazide 25 mg concomitantly with Nebicapone 50, 100, and 200 mg or placebo. Plasma concentrations of Nebicapone, levodopa, and 3-OMD were determined by HPLC. Blood samples (7 mL) for determination of plasma concentrations of levodopa, 3-OMD, and 2258 Nebicapone, as well as for the assay of S-COMT activity, were collected in potassium EDTA test tubes at the following times: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose. S-COMT activity was assessed as the amount of metanephrine formed by the action of S-COMT on an epinephrine substrate. Spontaneously reported clinical adverse events (AEs) were recorded throughout the study. Results: Sixteen subjects (8 females, 8 males; mean [SD] age, 26.13 [6.29] years; weight, 69.4 [12.4] kg; body mass index, 24.0 [3.0] kg/m 2 ) completed the 4 treatment periods and had data available for pharmacokinetic and pharmacodynamic analyses. Compared with placebo, levodopa C max increased 25%, 30%, and 34%, and AUC increased 14%, 37%, and 42% after administration of Nebicapone 50, 100, and 200 mg, respectively. After administration of Nebicapone 50, 100, and 200 mg, 3-OMD C max decreased 44%, 57%, and 58%, and 3-OMD AUC 0–∞ decreased 33%, 37%, and 45%, respectively, compared with placebo. Extent of exposure to levodopa, as assessed by using AUC 0−t , increased with all doses of Nebicapone in relationship to placebo, but the difference did not reach statistical significance. This may be related to a relatively high inter-subject variability: %CVs ranged from 48.0% with Nebicapone 100 mg to 66.8% with placebo. Maximum S-COMT inhibition by Nebicapone occurred at ~1.5 hours postdose and ranged from 57% with Nebicapone 50 mg to 74% with Nebicapone 200 mg. There was an inverse correlation between plasma concentrations of Nebicapone and S-COMT activity; T max of Nebicapone plasma concentrations and time to occurrence of the maximum inhibition of S-COMT activity appeared to correlate. Nineteen AEs were reported; 8 were assessed by the investigator as possibly related to treatment. All AEs were mild in severity. There were no serious AEs or discontinuations due to AEs. No abnormalities in liver enzyme levels were found. Conclusions: When administered concomitantly with a single dose of controlled-release levodopa 100 mg/benserazide 25 mg, single doses of Nebicapone 50, 100, and 200 mg were well tolerated in these healthy adult volunteers, and dose dependently inhibited S-COMT activity and reduced 3-OMD formation compared with placebo. However, there was no significant difference in levodopa bioavailability.
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poster abstract 7 pharmacokinetic pharmacodynamic interaction between Nebicapone bia 3 202 and controlled release levodopa benserazide madopar hbs 125
Neurotherapeutics, 2008Co-Authors: Luís Pereira De Almeida, Teresa G. Nunes, Leonel Torrao, Rita Machado, Jose Francisco Rocha, R Costa, Manuel Vazdasilva, Carlos Lopes, A I Loureiro, Lyndon C. WrightAbstract:Background and Objective Nebicapone (formerly known as BIA 3-202) is a new catechol-O-methyltransferase (COMT) inhibitor in development as a levodopa-sparing agent to be used in levodopa-treated Parkinson disease patients. The objective of this study was to investigate the effect of single oral doses of Nebicapone (50 mg, 100 mg and 200 mg) on the levodopa and 3-O-methyldopa (3-OMD) systemic exposure and erythrocyte soluble COMT (S-COMT) activity when coadministered with a single-dose of controlled-release levodopa/benserazide 100/25 mg (Madopar HBS 125). Methods Double-blind, randomized, placebo-controlled, four-way crossover study in 16 healthy subjects, with a washout of 5 or more days between periods. Results Taking placebo as reference, levodopa AUC0-t geometric mean ratios (GMR) and 90% confidence intervals (90%CI) were 1.14 (0.83;1.65), 1.37 (0.91;1.80), and 1.42 (0.97;1.92) for Nebicapone 50 mg, 100 mg and 200 mg, respectively. Regarding 3-OMD, AUC0-t GMR and 90%CI were 0.67 (0.53;0.80), 0.63 (0.51;0.77), and 0.55 (0.49;0.75), respectively. Maximum S-COMT inhibition occurred at 1.5 h after the dose and ranged from 57% with Nebicapone 50 mg to 74% with Nebicapone 200 mg. There was an inverse correlation between plasma concentrations of Nebicapone and S-COMT activity, and Nebicapone tmax correlated well with tEmax of S-COMT inhibition. Treatments were well tolerated. Conclusions Single doses of 50 mg, 100 mg, and 200 mg of the novel COMT inhibitor Nebicapone dose-dependently and significantly inhibited S-COMT activity, increased the bioavailability of levodopa, and reduced the formation of 3-OMD, when administered concomitantly with controlled-release levodopa/benserazide 100/25 mg (Madopar HBS 125). Supported by BIAL-Portela & Ca SA.
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Poster Abstract #8: Effect of Nebicapone (BIA 3-202) on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Subjects
Neurotherapeutics, 2008Co-Authors: Luís Pereira De Almeida, Patrício Soares-da-silva, Teresa G. Nunes, Manuel Vaz-da-silva, Amílcar FalcãoAbstract:Background and Objective Nebicapone (BIA 3-202) is a new catechol- O -methyltransferase (COMT) inhibitor. Warfarin is a racemic mixture of the R - and S -enantiomers, with most of the anticoagulant activity attributable to S -warfarin. In vitro , Nebicapone showed an inhibitory effect upon CYP2C9, which is known to be responsible for the metabolism of S -warfarin. The objective of this study was to investigate the effect of Nebicapone on warfarin pharmacokinetics and pharmacodynamics. Methods In a single-center, open-label, randomized, two-way crossover study in 16 healthy volunteers, two treatment periods were separated by a washout period of 14 days. In one period, subjects received Nebicapone 200 mg thrice daily for 9 days, and a warfarin 25 mg single dose concomitantly with the Nebicapone morning dose on day 4 (Test). In the other period, a warfarin 25 mg single dose was administered alone (Reference). Results Regarding S -warfarin, mean C max and AUC 0- t were respectively 1644 ng/mL and 66,627 ng.h/mL after Test, and 1739 ng/mL and 70,178 ng.h/mL after Reference. The S -warfarin Test/Reference geometric mean ratio (GMR) and 90% confidence interval (90%CI) was 0.932 (0.845;1.028) for C max and 0.914 (0.875;0.954) for AUC 0- t . Regarding R -warfarin, mean C max and AUC 0- t were respectively 1619 ng/mL and 92,796 ng.h/mL after Test, and 1649 ng/mL and 73,597 ng.h/mL after Reference. The R -warfarin Test/Reference GMR and 90%CI was 0.973 (0.878;1.077) for C max and 1.247 (1.170;1.327) for AUC 0- t . No differences were found regarding the pharmacodynamic parameter INR. Conclusions Nebicapone showed no significant effect on the S -warfarin pharmacokinetics or on the coagulation endpoint (INR). A mild inhibition of the R -warfarin metabolism was found, but although the anticoagulant effect of R -warfarin is five times less potent than that of S -warfarin, the reported effect on R -warfarin metabolism is unlikely to be of clinical relevance. Supported by BIAL-Portela & C a SA.
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pharmacokinetic pharmacodynamic interaction between Nebicapone a novel catechol o methyltransferase inhibitor and controlled release levodopa carbidopa 200 mg 50 mg
Drugs in R & D, 2008Co-Authors: Manuel Vazdasilva, Teresa G. Nunes, Amílcar Falcão, Ana I. Loureiro, Leonel Torrao, Rita Machado, Jose Francisco Rocha, R Costa, Carlos Lopes, Lyndon C. WrightAbstract:Background and objectives: Levodopa is the most effective symptomatic treatment for Parkinson’s disease (PD), but its use is often associated with development of motor complications. These adverse responses to fluctuations in dopaminergic stimulation can be reduced by concomitant administration of a catechol-O-methyltransferase (COMT) inhibitor. Nebicapone is a new COMT inhibitor currently being developed for use as an adjunct to levodopa/dopa decarboxylase inhibitor in the treatment of PD. This article aimed to investigate the effect of single oral doses (50 mg, 100 mg and 200 mg) of Nebicapone on levodopa pharmacokinetics and erythrocyte-soluble COMT (S-COMT) activity when coadministered with a single dose of controlled-release (CR) levodopa/carbidopa 200 mg/50 mg (Sinemet® CR 200/50) in healthy subjects (n = 16).
Jose Francisco Rocha - One of the best experts on this subject based on the ideXlab platform.
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a double blind randomized placebo and active controlled study of Nebicapone for the treatment of motor fluctuations in parkinson s disease
CNS Neuroscience & Therapeutics, 2010Co-Authors: Joaquim J Ferreira, Luis Almeida, Teresa G. Nunes, Patricio Soaresdasilva, Jose Francisco Rocha, Olivier Rascol, Werner Poewe, Cristina SampaioAbstract:To determine the efficacy, safety and tolerability of Nebicapone, a new catechol-O-methyltransferase inhibitor for the treatment of motor fluctuations in Parkinson's disease (PD), we conducted a multicenter, randomized, 8-week double-blind, placebo- and active-controlled, parallel-group study comparing Nebicapone 50 mg, 100 mg, or 150 mg, entacapone 200 mg (active control) or placebo administered concomitantly with levodopa/carbidopa or levodopa/benserazide. Two hundred and fifty-two PD patients with motor fluctuations treated with levodopa/carbidopa or levodopa/benserazide (4-8 daily doses) were enrolled and 250 patients were eligible for intention-to-treat (ITT) analysis on the basis of having at least one efficacy assessment. The primary endpoint was 8-week change from baseline in absolute "Off" time duration noted in self-scoring diaries. At 8 weeks of treatment the mean daily "Off" time decreased significantly compared to placebo for Nebicapone 150 mg (-106 min; 95%CI: -192; -21) and entacapone 200 mg (-81 min; 95%CI: -142; -19). The decrease in "Off" time with Nebicapone 50 mg or 100 mg did not reach statistical significance. Treatment-emergent adverse events were reported by 32% to 49% of patients in any treatment group, with no observed dose relationship in the Nebicapone groups. Clinically relevant elevations in aspartate transaminase (AST) and/or alanine transaminase (ALT) were observed in 4 of 46 patients with the Nebicapone 150 mg dose. The results of this study show that Nebicapone 150 mg is efficacious for the treatment of motor fluctuations in PD patients. However, the risk of increasing liver transaminases and its clinically relevance deserves further evaluation.
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pharmacokinetic pharmacodynamic interaction between Nebicapone and controlled release levodopa benserazide a single center phase i double blind randomized placebo controlled four way crossover study in healthy subjects
Clinical Therapeutics, 2009Co-Authors: Teresa G. Nunes, Amílcar Falcão, Ana I. Loureiro, Leonel Torrao, Carlos Fernandeslopes, Rita Machado, Jose Francisco Rocha, R Costa, Manuel Vazdasilva, Lyndon C. WrightAbstract:Abstract Background: Nebicapone is a reversible catechol-O-methyltransferase (COMT) inhibitor. Coadministration of a COMT inhibitor with levodopa and a dopa-decarboxylase inhibitor (carbidopa or benserazide) increases levodopa exposure and its therapeutic effect. Objectives: The primary objective of this study was to investigate the effect of Nebicapone (50, 100, and 200 mg), compared with placebo, on levodopa pharmacokinetics when coadministered with a single dose of controlled-release levodopa 100 mg/benserazide 25 mg. The secondary objectives were to investigate the effect of Nebicapone on the erythrocyte-soluble COMT (S-COMT) activity and on the plasma levels of the levodopa 3- O -methylated metabolite (3- O -methyldopa [3-OMD]). Nebicapone's tolerability was also assessed. Methods: This was a single-center, Phase I, doubleblind, randomized, placebo-controlled, 4-way crossover study conducted in healthy adult volunteers. Each of the 4 single-dose treatment periods was separated by a washout period of ≥5 days. During the different treatment periods, subjects received a single dose of controlled-release levodopa 100 mg/benserazide 25 mg concomitantly with Nebicapone 50, 100, and 200 mg or placebo. Plasma concentrations of Nebicapone, levodopa, and 3-OMD were determined by HPLC. Blood samples (7 mL) for determination of plasma concentrations of levodopa, 3-OMD, and 2258 Nebicapone, as well as for the assay of S-COMT activity, were collected in potassium EDTA test tubes at the following times: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose. S-COMT activity was assessed as the amount of metanephrine formed by the action of S-COMT on an epinephrine substrate. Spontaneously reported clinical adverse events (AEs) were recorded throughout the study. Results: Sixteen subjects (8 females, 8 males; mean [SD] age, 26.13 [6.29] years; weight, 69.4 [12.4] kg; body mass index, 24.0 [3.0] kg/m 2 ) completed the 4 treatment periods and had data available for pharmacokinetic and pharmacodynamic analyses. Compared with placebo, levodopa C max increased 25%, 30%, and 34%, and AUC increased 14%, 37%, and 42% after administration of Nebicapone 50, 100, and 200 mg, respectively. After administration of Nebicapone 50, 100, and 200 mg, 3-OMD C max decreased 44%, 57%, and 58%, and 3-OMD AUC 0–∞ decreased 33%, 37%, and 45%, respectively, compared with placebo. Extent of exposure to levodopa, as assessed by using AUC 0−t , increased with all doses of Nebicapone in relationship to placebo, but the difference did not reach statistical significance. This may be related to a relatively high inter-subject variability: %CVs ranged from 48.0% with Nebicapone 100 mg to 66.8% with placebo. Maximum S-COMT inhibition by Nebicapone occurred at ~1.5 hours postdose and ranged from 57% with Nebicapone 50 mg to 74% with Nebicapone 200 mg. There was an inverse correlation between plasma concentrations of Nebicapone and S-COMT activity; T max of Nebicapone plasma concentrations and time to occurrence of the maximum inhibition of S-COMT activity appeared to correlate. Nineteen AEs were reported; 8 were assessed by the investigator as possibly related to treatment. All AEs were mild in severity. There were no serious AEs or discontinuations due to AEs. No abnormalities in liver enzyme levels were found. Conclusions: When administered concomitantly with a single dose of controlled-release levodopa 100 mg/benserazide 25 mg, single doses of Nebicapone 50, 100, and 200 mg were well tolerated in these healthy adult volunteers, and dose dependently inhibited S-COMT activity and reduced 3-OMD formation compared with placebo. However, there was no significant difference in levodopa bioavailability.
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Effect of Nebicapone on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects
European Journal of Clinical Pharmacology, 2008Co-Authors: Luis Almeida, Manuel Vaz-da-silva, Amílcar Falcão, Jose Francisco Rocha, Teresa Nunes, Ana-teresa Santos, Carla Neta, Tice Macedo, C. Fontes-ribeiro, P. Soares-da-silvaAbstract:Objective Nebicapone is a new catechol-O-methyltransferase inhibitor. In vitro, Nebicapone has showed an inhibitory effect upon CYP2C9, which is responsible for the metabolism of S-warfarin. The objective of this study was to investigate the effect of Nebicapone on warfarin pharmacokinetics and pharmacodynamics in healthy subjects. Methods Single-centre, open-label, randomised, two-period crossover study in 16 healthy volunteers. In one period, subjects received Nebicapone 200 mg thrice daily for 9 days and a racemic warfarin 25-mg single dose concomitantly with the Nebicapone morning dose on day 4 (test). In the other period, subjects received a racemic warfarin 25-mg single dose alone (reference). The treatment periods were separated by a washout of 14 days. Results For R-warfarin, mean ± SD C_max was 1,619 ± 284 ng/mL for test and 1,649 ± 357 ng/mL for reference, while AUC_0- t was 92,796 ± 18,976 ng·h/mL (test) and 73,597 ± 11,363 ng·h/mL (reference). The R-warfarin test-to-reference geometric mean ratio (GMR) and 90% confidence interval (90%CI) were 0.973 (0.878–1.077) for C_max and 1.247 (1.170–1.327) for AUC_0- t . For S-warfarin, mean ± SD C_max was 1,644 ± 331 ng/mL for test and 1,739 ± 392 ng/mL for reference, while AUC_0- t was 66,627 ± 41,199 ng·h/mL (test) and 70,178 ± 42,560 ng·h/mL (reference). The S-warfarin test-to-reference GMR and 90%CI were 0.932 (0.845–1.028) for C_max and 0.914 (0.875–0.954) for AUC_0- t . No differences were found for the pharmacodynamic parameter (INR). Conclusion Nebicapone showed no significant effect on S-warfarin pharmacokinetics or on the coagulation endpoint (INR). A mild inhibition of the R-warfarin metabolism was found but is unlikely to be of clinical relevance.
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poster abstract 7 pharmacokinetic pharmacodynamic interaction between Nebicapone bia 3 202 and controlled release levodopa benserazide madopar hbs 125
Neurotherapeutics, 2008Co-Authors: Luís Pereira De Almeida, Teresa G. Nunes, Leonel Torrao, Rita Machado, Jose Francisco Rocha, R Costa, Manuel Vazdasilva, Carlos Lopes, A I Loureiro, Lyndon C. WrightAbstract:Background and Objective Nebicapone (formerly known as BIA 3-202) is a new catechol-O-methyltransferase (COMT) inhibitor in development as a levodopa-sparing agent to be used in levodopa-treated Parkinson disease patients. The objective of this study was to investigate the effect of single oral doses of Nebicapone (50 mg, 100 mg and 200 mg) on the levodopa and 3-O-methyldopa (3-OMD) systemic exposure and erythrocyte soluble COMT (S-COMT) activity when coadministered with a single-dose of controlled-release levodopa/benserazide 100/25 mg (Madopar HBS 125). Methods Double-blind, randomized, placebo-controlled, four-way crossover study in 16 healthy subjects, with a washout of 5 or more days between periods. Results Taking placebo as reference, levodopa AUC0-t geometric mean ratios (GMR) and 90% confidence intervals (90%CI) were 1.14 (0.83;1.65), 1.37 (0.91;1.80), and 1.42 (0.97;1.92) for Nebicapone 50 mg, 100 mg and 200 mg, respectively. Regarding 3-OMD, AUC0-t GMR and 90%CI were 0.67 (0.53;0.80), 0.63 (0.51;0.77), and 0.55 (0.49;0.75), respectively. Maximum S-COMT inhibition occurred at 1.5 h after the dose and ranged from 57% with Nebicapone 50 mg to 74% with Nebicapone 200 mg. There was an inverse correlation between plasma concentrations of Nebicapone and S-COMT activity, and Nebicapone tmax correlated well with tEmax of S-COMT inhibition. Treatments were well tolerated. Conclusions Single doses of 50 mg, 100 mg, and 200 mg of the novel COMT inhibitor Nebicapone dose-dependently and significantly inhibited S-COMT activity, increased the bioavailability of levodopa, and reduced the formation of 3-OMD, when administered concomitantly with controlled-release levodopa/benserazide 100/25 mg (Madopar HBS 125). Supported by BIAL-Portela & Ca SA.
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pharmacokinetic pharmacodynamic interaction between Nebicapone a novel catechol o methyltransferase inhibitor and controlled release levodopa carbidopa 200 mg 50 mg
Drugs in R & D, 2008Co-Authors: Manuel Vazdasilva, Teresa G. Nunes, Amílcar Falcão, Ana I. Loureiro, Leonel Torrao, Rita Machado, Jose Francisco Rocha, R Costa, Carlos Lopes, Lyndon C. WrightAbstract:Background and objectives: Levodopa is the most effective symptomatic treatment for Parkinson’s disease (PD), but its use is often associated with development of motor complications. These adverse responses to fluctuations in dopaminergic stimulation can be reduced by concomitant administration of a catechol-O-methyltransferase (COMT) inhibitor. Nebicapone is a new COMT inhibitor currently being developed for use as an adjunct to levodopa/dopa decarboxylase inhibitor in the treatment of PD. This article aimed to investigate the effect of single oral doses (50 mg, 100 mg and 200 mg) of Nebicapone on levodopa pharmacokinetics and erythrocyte-soluble COMT (S-COMT) activity when coadministered with a single dose of controlled-release (CR) levodopa/carbidopa 200 mg/50 mg (Sinemet® CR 200/50) in healthy subjects (n = 16).
Luís Pereira De Almeida - One of the best experts on this subject based on the ideXlab platform.
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Chronopharmacology of Nebicapone, a new catechol-O-methyltransferase inhibitor
Current medical research and opinion, 2010Co-Authors: Luís Pereira De Almeida, Manuel Vaz-da-silva, Amílcar Falcão, Ana I. Loureiro, Carlos Fernandes-lopes, Lyndon C. Wright, Joana Maia, Leonel Torrao, Bruno Igreja, Patrício Soares-da-silvaAbstract:Objective: To investigate the chronopharmacology of Nebicapone, a new catechol-O-methyltransferase (COMT) inhibitor currently being developed for use as an adjunct to levodopa/carbidopa or levodopa/benserazide in the treatment of Parkinson’s disease. Methods: This was a double-blind, randomised, placebo-controlled, parallel-group study. Eighteen Caucasian subjects were randomly assigned to treatment with either Nebicapone 100 mg (n ¼ 6), Nebicapone 200 mg (n ¼ 6) or placebo (n ¼ 6) at 4-h intervals for 7 days. First dose occurred at 8:00 AM on day 1 and last dose at 8:00 AM on day 8. Blood samples for the determination of plasma drug concentrations of Nebicapone and its glucuronidated and methylated metabolites and for the assay of erythrocyte soluble COMT (S-COMT) activity were taken at frequent times following the first and last doses, and before the 8:00 AM and 8:00 PM doses on days 2–7. Results:
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poster abstract 6 absorption distribution metabolism and excretion of 14c labeled Nebicapone bia 3 202 and metabolites
Neurotherapeutics, 2008Co-Authors: Luís Pereira De Almeida, Joana Maia, Patricio SoaresdasilvaAbstract:Background and Objective Nebicapone [BIA 3-202; 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone] is a reversible catechol- O -methyltransferase (COMT) inhibitor developed to extend duration of action of levodopa in therapy of Parkinson's disease. The objective of this study was to investigate absorption, distribution, metabolism, and excretion of [ 14 C]Nebicapone and metabolites. Methods In this open-label study, a single dose of 2.29 MBq 14 C-labeled Nebicapone (200 mg) was orally administered to four healthy male volunteers. Results Metabolites were identified in plasma (8), urine (22), and feces (4), with BIA 3-476 (glucuronide) as the ubiquitous major metabolite. The plasma concentration–time profile of [ 14 C]Nebicapone demonstrated t max 1.25±0.65 h, t 1/2 134.55±25.67 h, C max 19,647.02±4930.20 ng-eq/g, AUC 0- t 161,735.51±9224.66 h.ng-eq/g, and AUC 0– 199,603.30±16,854.08 h.ng-eq/g. For whole blood, the values were t max 1.00±0.41 h, t 1/2 32.98±22.82 h, C max 8411.21±1628.35 ng-eq/g, AUC 0- t 35,539.23±13,664.87 h.ng-eq/g, and AUC 0– 36,970.64±14,559.17 h.ng-eq/g. Plasma pharmacokinetics of Nebicapone demonstrated t max 1.00±0.41 h, t 1/2 2.34±0.51 h, C max 12,650.00±2898.85 ng-eq/g, AUC 0- t 18,719.96±734.18 h.ng-eq/g, AUC 0– 18,392.12±753.81 h.ng-eq/g. BIA 3-476 demonstrated t max 1.25±0.50 h, t 1/2 3.47±0.68 h, C max 15,250±2563.20 ng-eq/g, AUC 0- t 53,810.61±7358.81 h.ng-eq/g, AUC 0– 54,541.21±7135.70 h.ng-eq/g. BIA 3-270 (methylated metabolite) demonstrated t max 21.01±6.01 h, t 1/2 103.43±6.01 h, C max 286.25±20.48 ng-eq/g, AUC 0- t 27,641.89±4569.99 h.ng-eq/g, AUC 0– 36,968.12±4294.42 h.ng-eq/g. Thus Nebicapone and BIA 3-476 account for most of the early phase circulating Nebicapone-derived moieties, have limited circulating cell association, peak concentrations shortly after dosing, and short body residence. Longer terminal half-life phases were dominated by low concentrations of BIA 3-270. Urinary excretion, mainly as BIA 3-476, accounted for approximately 79% of recovered radioactivity or 70.1% of the administered dose, with excretion of unchanged Nebicapone insignificant ( Conclusions The primary metabolic pathway of Nebicapone is glucuronidation. The kidney is the principal route of excretion of Nebicapone metabolites. Supported by BIAL-Portela & C a SA.
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poster abstract 7 pharmacokinetic pharmacodynamic interaction between Nebicapone bia 3 202 and controlled release levodopa benserazide madopar hbs 125
Neurotherapeutics, 2008Co-Authors: Luís Pereira De Almeida, Teresa G. Nunes, Leonel Torrao, Rita Machado, Jose Francisco Rocha, R Costa, Manuel Vazdasilva, Carlos Lopes, A I Loureiro, Lyndon C. WrightAbstract:Background and Objective Nebicapone (formerly known as BIA 3-202) is a new catechol-O-methyltransferase (COMT) inhibitor in development as a levodopa-sparing agent to be used in levodopa-treated Parkinson disease patients. The objective of this study was to investigate the effect of single oral doses of Nebicapone (50 mg, 100 mg and 200 mg) on the levodopa and 3-O-methyldopa (3-OMD) systemic exposure and erythrocyte soluble COMT (S-COMT) activity when coadministered with a single-dose of controlled-release levodopa/benserazide 100/25 mg (Madopar HBS 125). Methods Double-blind, randomized, placebo-controlled, four-way crossover study in 16 healthy subjects, with a washout of 5 or more days between periods. Results Taking placebo as reference, levodopa AUC0-t geometric mean ratios (GMR) and 90% confidence intervals (90%CI) were 1.14 (0.83;1.65), 1.37 (0.91;1.80), and 1.42 (0.97;1.92) for Nebicapone 50 mg, 100 mg and 200 mg, respectively. Regarding 3-OMD, AUC0-t GMR and 90%CI were 0.67 (0.53;0.80), 0.63 (0.51;0.77), and 0.55 (0.49;0.75), respectively. Maximum S-COMT inhibition occurred at 1.5 h after the dose and ranged from 57% with Nebicapone 50 mg to 74% with Nebicapone 200 mg. There was an inverse correlation between plasma concentrations of Nebicapone and S-COMT activity, and Nebicapone tmax correlated well with tEmax of S-COMT inhibition. Treatments were well tolerated. Conclusions Single doses of 50 mg, 100 mg, and 200 mg of the novel COMT inhibitor Nebicapone dose-dependently and significantly inhibited S-COMT activity, increased the bioavailability of levodopa, and reduced the formation of 3-OMD, when administered concomitantly with controlled-release levodopa/benserazide 100/25 mg (Madopar HBS 125). Supported by BIAL-Portela & Ca SA.
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Poster Abstract #8: Effect of Nebicapone (BIA 3-202) on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Subjects
Neurotherapeutics, 2008Co-Authors: Luís Pereira De Almeida, Patrício Soares-da-silva, Teresa G. Nunes, Manuel Vaz-da-silva, Amílcar FalcãoAbstract:Background and Objective Nebicapone (BIA 3-202) is a new catechol- O -methyltransferase (COMT) inhibitor. Warfarin is a racemic mixture of the R - and S -enantiomers, with most of the anticoagulant activity attributable to S -warfarin. In vitro , Nebicapone showed an inhibitory effect upon CYP2C9, which is known to be responsible for the metabolism of S -warfarin. The objective of this study was to investigate the effect of Nebicapone on warfarin pharmacokinetics and pharmacodynamics. Methods In a single-center, open-label, randomized, two-way crossover study in 16 healthy volunteers, two treatment periods were separated by a washout period of 14 days. In one period, subjects received Nebicapone 200 mg thrice daily for 9 days, and a warfarin 25 mg single dose concomitantly with the Nebicapone morning dose on day 4 (Test). In the other period, a warfarin 25 mg single dose was administered alone (Reference). Results Regarding S -warfarin, mean C max and AUC 0- t were respectively 1644 ng/mL and 66,627 ng.h/mL after Test, and 1739 ng/mL and 70,178 ng.h/mL after Reference. The S -warfarin Test/Reference geometric mean ratio (GMR) and 90% confidence interval (90%CI) was 0.932 (0.845;1.028) for C max and 0.914 (0.875;0.954) for AUC 0- t . Regarding R -warfarin, mean C max and AUC 0- t were respectively 1619 ng/mL and 92,796 ng.h/mL after Test, and 1649 ng/mL and 73,597 ng.h/mL after Reference. The R -warfarin Test/Reference GMR and 90%CI was 0.973 (0.878;1.077) for C max and 1.247 (1.170;1.327) for AUC 0- t . No differences were found regarding the pharmacodynamic parameter INR. Conclusions Nebicapone showed no significant effect on the S -warfarin pharmacokinetics or on the coagulation endpoint (INR). A mild inhibition of the R -warfarin metabolism was found, but although the anticoagulant effect of R -warfarin is five times less potent than that of S -warfarin, the reported effect on R -warfarin metabolism is unlikely to be of clinical relevance. Supported by BIAL-Portela & C a SA.
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effects of Nebicapone on levodopa pharmacokinetics catechol o methyltransferase activity and motor fluctuations in patients with parkinson disease
Clinical Neuropharmacology, 2008Co-Authors: Joaquim J Ferreira, Luís Pereira De Almeida, L Cunha, Marina Ticmeanu, Mario M Rosa, Cristina Januario, Cristinaelena Mitu, Miguel Coelho, Leonor Correiaguedes, Ana MorgadinhoAbstract:Objective: To investigate the effects of Nebicapone, a new catechol-O-methyltransferase (COMT) inhibitor, on levodopa pharmacokinetics, COMT activity, and motor fluctuations in Parkinson disease in comparison to placebo and entacapone.
Amílcar Falcão - One of the best experts on this subject based on the ideXlab platform.
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Chronopharmacology of Nebicapone, a new catechol-O-methyltransferase inhibitor
Current medical research and opinion, 2010Co-Authors: Luís Pereira De Almeida, Manuel Vaz-da-silva, Amílcar Falcão, Ana I. Loureiro, Carlos Fernandes-lopes, Lyndon C. Wright, Joana Maia, Leonel Torrao, Bruno Igreja, Patrício Soares-da-silvaAbstract:Objective: To investigate the chronopharmacology of Nebicapone, a new catechol-O-methyltransferase (COMT) inhibitor currently being developed for use as an adjunct to levodopa/carbidopa or levodopa/benserazide in the treatment of Parkinson’s disease. Methods: This was a double-blind, randomised, placebo-controlled, parallel-group study. Eighteen Caucasian subjects were randomly assigned to treatment with either Nebicapone 100 mg (n ¼ 6), Nebicapone 200 mg (n ¼ 6) or placebo (n ¼ 6) at 4-h intervals for 7 days. First dose occurred at 8:00 AM on day 1 and last dose at 8:00 AM on day 8. Blood samples for the determination of plasma drug concentrations of Nebicapone and its glucuronidated and methylated metabolites and for the assay of erythrocyte soluble COMT (S-COMT) activity were taken at frequent times following the first and last doses, and before the 8:00 AM and 8:00 PM doses on days 2–7. Results:
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pharmacokinetic pharmacodynamic interaction between Nebicapone and controlled release levodopa benserazide a single center phase i double blind randomized placebo controlled four way crossover study in healthy subjects
Clinical Therapeutics, 2009Co-Authors: Teresa G. Nunes, Amílcar Falcão, Ana I. Loureiro, Leonel Torrao, Carlos Fernandeslopes, Rita Machado, Jose Francisco Rocha, R Costa, Manuel Vazdasilva, Lyndon C. WrightAbstract:Abstract Background: Nebicapone is a reversible catechol-O-methyltransferase (COMT) inhibitor. Coadministration of a COMT inhibitor with levodopa and a dopa-decarboxylase inhibitor (carbidopa or benserazide) increases levodopa exposure and its therapeutic effect. Objectives: The primary objective of this study was to investigate the effect of Nebicapone (50, 100, and 200 mg), compared with placebo, on levodopa pharmacokinetics when coadministered with a single dose of controlled-release levodopa 100 mg/benserazide 25 mg. The secondary objectives were to investigate the effect of Nebicapone on the erythrocyte-soluble COMT (S-COMT) activity and on the plasma levels of the levodopa 3- O -methylated metabolite (3- O -methyldopa [3-OMD]). Nebicapone's tolerability was also assessed. Methods: This was a single-center, Phase I, doubleblind, randomized, placebo-controlled, 4-way crossover study conducted in healthy adult volunteers. Each of the 4 single-dose treatment periods was separated by a washout period of ≥5 days. During the different treatment periods, subjects received a single dose of controlled-release levodopa 100 mg/benserazide 25 mg concomitantly with Nebicapone 50, 100, and 200 mg or placebo. Plasma concentrations of Nebicapone, levodopa, and 3-OMD were determined by HPLC. Blood samples (7 mL) for determination of plasma concentrations of levodopa, 3-OMD, and 2258 Nebicapone, as well as for the assay of S-COMT activity, were collected in potassium EDTA test tubes at the following times: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose. S-COMT activity was assessed as the amount of metanephrine formed by the action of S-COMT on an epinephrine substrate. Spontaneously reported clinical adverse events (AEs) were recorded throughout the study. Results: Sixteen subjects (8 females, 8 males; mean [SD] age, 26.13 [6.29] years; weight, 69.4 [12.4] kg; body mass index, 24.0 [3.0] kg/m 2 ) completed the 4 treatment periods and had data available for pharmacokinetic and pharmacodynamic analyses. Compared with placebo, levodopa C max increased 25%, 30%, and 34%, and AUC increased 14%, 37%, and 42% after administration of Nebicapone 50, 100, and 200 mg, respectively. After administration of Nebicapone 50, 100, and 200 mg, 3-OMD C max decreased 44%, 57%, and 58%, and 3-OMD AUC 0–∞ decreased 33%, 37%, and 45%, respectively, compared with placebo. Extent of exposure to levodopa, as assessed by using AUC 0−t , increased with all doses of Nebicapone in relationship to placebo, but the difference did not reach statistical significance. This may be related to a relatively high inter-subject variability: %CVs ranged from 48.0% with Nebicapone 100 mg to 66.8% with placebo. Maximum S-COMT inhibition by Nebicapone occurred at ~1.5 hours postdose and ranged from 57% with Nebicapone 50 mg to 74% with Nebicapone 200 mg. There was an inverse correlation between plasma concentrations of Nebicapone and S-COMT activity; T max of Nebicapone plasma concentrations and time to occurrence of the maximum inhibition of S-COMT activity appeared to correlate. Nineteen AEs were reported; 8 were assessed by the investigator as possibly related to treatment. All AEs were mild in severity. There were no serious AEs or discontinuations due to AEs. No abnormalities in liver enzyme levels were found. Conclusions: When administered concomitantly with a single dose of controlled-release levodopa 100 mg/benserazide 25 mg, single doses of Nebicapone 50, 100, and 200 mg were well tolerated in these healthy adult volunteers, and dose dependently inhibited S-COMT activity and reduced 3-OMD formation compared with placebo. However, there was no significant difference in levodopa bioavailability.
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Effect of Nebicapone on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects
European Journal of Clinical Pharmacology, 2008Co-Authors: Luis Almeida, Manuel Vaz-da-silva, Amílcar Falcão, Jose Francisco Rocha, Teresa Nunes, Ana-teresa Santos, Carla Neta, Tice Macedo, C. Fontes-ribeiro, P. Soares-da-silvaAbstract:Objective Nebicapone is a new catechol-O-methyltransferase inhibitor. In vitro, Nebicapone has showed an inhibitory effect upon CYP2C9, which is responsible for the metabolism of S-warfarin. The objective of this study was to investigate the effect of Nebicapone on warfarin pharmacokinetics and pharmacodynamics in healthy subjects. Methods Single-centre, open-label, randomised, two-period crossover study in 16 healthy volunteers. In one period, subjects received Nebicapone 200 mg thrice daily for 9 days and a racemic warfarin 25-mg single dose concomitantly with the Nebicapone morning dose on day 4 (test). In the other period, subjects received a racemic warfarin 25-mg single dose alone (reference). The treatment periods were separated by a washout of 14 days. Results For R-warfarin, mean ± SD C_max was 1,619 ± 284 ng/mL for test and 1,649 ± 357 ng/mL for reference, while AUC_0- t was 92,796 ± 18,976 ng·h/mL (test) and 73,597 ± 11,363 ng·h/mL (reference). The R-warfarin test-to-reference geometric mean ratio (GMR) and 90% confidence interval (90%CI) were 0.973 (0.878–1.077) for C_max and 1.247 (1.170–1.327) for AUC_0- t . For S-warfarin, mean ± SD C_max was 1,644 ± 331 ng/mL for test and 1,739 ± 392 ng/mL for reference, while AUC_0- t was 66,627 ± 41,199 ng·h/mL (test) and 70,178 ± 42,560 ng·h/mL (reference). The S-warfarin test-to-reference GMR and 90%CI were 0.932 (0.845–1.028) for C_max and 0.914 (0.875–0.954) for AUC_0- t . No differences were found for the pharmacodynamic parameter (INR). Conclusion Nebicapone showed no significant effect on S-warfarin pharmacokinetics or on the coagulation endpoint (INR). A mild inhibition of the R-warfarin metabolism was found but is unlikely to be of clinical relevance.
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Poster Abstract #8: Effect of Nebicapone (BIA 3-202) on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Subjects
Neurotherapeutics, 2008Co-Authors: Luís Pereira De Almeida, Patrício Soares-da-silva, Teresa G. Nunes, Manuel Vaz-da-silva, Amílcar FalcãoAbstract:Background and Objective Nebicapone (BIA 3-202) is a new catechol- O -methyltransferase (COMT) inhibitor. Warfarin is a racemic mixture of the R - and S -enantiomers, with most of the anticoagulant activity attributable to S -warfarin. In vitro , Nebicapone showed an inhibitory effect upon CYP2C9, which is known to be responsible for the metabolism of S -warfarin. The objective of this study was to investigate the effect of Nebicapone on warfarin pharmacokinetics and pharmacodynamics. Methods In a single-center, open-label, randomized, two-way crossover study in 16 healthy volunteers, two treatment periods were separated by a washout period of 14 days. In one period, subjects received Nebicapone 200 mg thrice daily for 9 days, and a warfarin 25 mg single dose concomitantly with the Nebicapone morning dose on day 4 (Test). In the other period, a warfarin 25 mg single dose was administered alone (Reference). Results Regarding S -warfarin, mean C max and AUC 0- t were respectively 1644 ng/mL and 66,627 ng.h/mL after Test, and 1739 ng/mL and 70,178 ng.h/mL after Reference. The S -warfarin Test/Reference geometric mean ratio (GMR) and 90% confidence interval (90%CI) was 0.932 (0.845;1.028) for C max and 0.914 (0.875;0.954) for AUC 0- t . Regarding R -warfarin, mean C max and AUC 0- t were respectively 1619 ng/mL and 92,796 ng.h/mL after Test, and 1649 ng/mL and 73,597 ng.h/mL after Reference. The R -warfarin Test/Reference GMR and 90%CI was 0.973 (0.878;1.077) for C max and 1.247 (1.170;1.327) for AUC 0- t . No differences were found regarding the pharmacodynamic parameter INR. Conclusions Nebicapone showed no significant effect on the S -warfarin pharmacokinetics or on the coagulation endpoint (INR). A mild inhibition of the R -warfarin metabolism was found, but although the anticoagulant effect of R -warfarin is five times less potent than that of S -warfarin, the reported effect on R -warfarin metabolism is unlikely to be of clinical relevance. Supported by BIAL-Portela & C a SA.
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pharmacokinetic pharmacodynamic interaction between Nebicapone a novel catechol o methyltransferase inhibitor and controlled release levodopa carbidopa 200 mg 50 mg
Drugs in R & D, 2008Co-Authors: Manuel Vazdasilva, Teresa G. Nunes, Amílcar Falcão, Ana I. Loureiro, Leonel Torrao, Rita Machado, Jose Francisco Rocha, R Costa, Carlos Lopes, Lyndon C. WrightAbstract:Background and objectives: Levodopa is the most effective symptomatic treatment for Parkinson’s disease (PD), but its use is often associated with development of motor complications. These adverse responses to fluctuations in dopaminergic stimulation can be reduced by concomitant administration of a catechol-O-methyltransferase (COMT) inhibitor. Nebicapone is a new COMT inhibitor currently being developed for use as an adjunct to levodopa/dopa decarboxylase inhibitor in the treatment of PD. This article aimed to investigate the effect of single oral doses (50 mg, 100 mg and 200 mg) of Nebicapone on levodopa pharmacokinetics and erythrocyte-soluble COMT (S-COMT) activity when coadministered with a single dose of controlled-release (CR) levodopa/carbidopa 200 mg/50 mg (Sinemet® CR 200/50) in healthy subjects (n = 16).
