title: Pharmacokinetic-pharmacodynamic interaction between nebicapone, a novel catechol-o-methyltransferase inhibitor, and controlled-release levodopa/carbidopa 200 mg/50 mg : randomized, double-blind, placebo-controlled, crossover study in healthy subjects.
abstract: OBJECTIVE
  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((R)) CR 200/50) in healthy subjects (n = 16).
  
  
  METHODS
  This was a randomized, double-blind, placebo-controlled, four-way crossover study in healthy subjects, with at least 5 days of washout between treatment periods.
  
  
  RESULTS
  There was a dose-dependent and significant increase in levodopa extent of exposure (area under the plasma concentration-time curve from time zero to infinity [AUC(infinity)]) without a significant change in peak exposure (maximum plasma concentration; [C(max)]). Using placebo as a reference, levodopa geometric mean ratios (GMRs) and 90% CIs following nebicapone 50 mg, 100 mg and 200 mg were, respectively, 1.13 (0.98, 1.30), 1.04 (0.90, 1.19) and 1.10 (0.96, 1.27) for C(max) and 1.26 (1.16, 1.34), 1.37 (1.27, 1.75) and 1.47 (1.42, 1.65) for AUC(infinity). For 3-O-methyldopa (3-OMD), the GMRs and 90% CIs were, respectively, 0.61 (0.55, 0.67), 0.45 (0.41, 0.50) and 0.33 (0.30, 0.36) for C(max) and 0.69 (0.61, 0.78), 0.53 (0.41, 0.61) and 0.41 (0.37, 0.47) for AUC(infinity). Nebicapone dose dependently and significantly decreased COMT activity. Maximum COMT inhibition occurred at 1.5-2.4 hours post-dose and ranged from 56% to 73% with nebicapone 50 mg and 200 mg, respectively. There was a good correlation between plasma concentrations of nebicapone and inhibition of S-COMT activity. Treatments were well tolerated.
  
  
  CONCLUSIONS
  Following concomitant administration with levodopa/carbidopa CR 200 mg/50 mg, single doses of nebicapone 50 mg, 100 mg and 200 mg significantly and dose-dependently inhibited S-COMT activity, increased systemic exposure to levodopa, and reduced 3-OMD formation.
authors.affiliation: Department of Research & Development, BIAL, S. Mamede do Coronado, Trofa, Portugal.
authors.forename: Manuel
authors.initials: M
authors.lastname: Vaz-da-Silva
authors.forename: Ana I
authors.initials: AI
authors.lastname: Loureiro
authors.forename: Teresa
authors.initials: T
authors.lastname: Nunes
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopes
authors.forename: José
authors.initials: J
authors.lastname: Rocha
authors.forename: Rita
authors.initials: R
authors.lastname: Machado
authors.forename: Raquel
authors.initials: R
authors.lastname: Costa
authors.forename: Leonel
authors.initials: L
authors.lastname: Torrão
authors.forename: Amílcar
authors.initials: A
authors.lastname: Falcão
authors.forename: Lyndon
authors.initials: L
authors.lastname: Wright
authors.forename: Luis
authors.initials: L
authors.lastname: Almeida
authors.forename: Patrício
authors.initials: P
authors.lastname: Soares-da-Silva
mesh_terms: D000098:Acetophenones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000328:Adult; D000978:Antiparkinson Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D002230:Carbidopa / Q000008:administration & dosage / Q000009:adverse effects; D065098:Catechol O-Methyltransferase Inhibitors; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007980:Levodopa / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D000098:Acetophenones; D000978:Antiparkinson Agents; D065098:Catechol O-Methyltransferase Inhibitors; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D014443:Tyrosine; D007980:Levodopa; D002230:Carbidopa; C433466:nebicapone; C008404:3-methoxytyrosine