title: Pharmacokinetics and pharmacodynamics of BIA 3-202, a novel COMT inhibitor, during first administration to humans.
abstract: OBJECTIVE
  To determine the tolerability, pharmacodynamics and pharmacokinetics of single oral doses of BIA 3-202, a novel catechol-O-methyltransferase (COMT) inhibitor, in healthy male volunteers.
  
  
  METHODS
  Single increasing oral doses of BIA 3-202 (10, 30, 50, 100, 200, 400 and 800mg) were administered under fasting conditions to seven sequential groups of nine subjects, under a double-blind, randomised, placebo-controlled design. In an additional group of eight subjects (group 8), a single dose of BIA 3-202 400mg was administered on two occasions, once under fasting conditions and once with a high-fat meal, under an open-label, two-way crossover design.
  
  
  RESULTS
  BIA 3-202 was well tolerated at all doses tested. Most adverse events were mild in severity and their incidence was similar between BIA 3-202 and placebo. Maximum plasma concentrations (C(max)) of BIA 3-202 were attained at 0.5-2.5h (t(max)) and thereafter declined with an apparent terminal half-life (t(1/2)) of 1.5-5h. Over the dose range of 10-800mg, there was an approximately dose-proportional increase in the area under the plasma concentration-time curve (AUC) values of BIA 3-202: for a dose level increase in the ratio 3.0:1.7:2.0:2.0:2.0:2.0, AUC increased in the ratio 3.1:1.7:1.9:2.2:2.1:1.7. Plasma concentrations of the O-methylated derivative, BIA 3-270, increased markedly less than predicted from a proportional relationship: for a dose level increase in the ratio 1:80, AUC(0-t )increased in the ratio 1:5. In most subjects, the t(max) of BIA 3-270 was attained at the last sampling time and, therefore, t(1/2 )could not be estimated. Urine assays showed that less than 1% of the total dose administered was excreted in urine as BIA 3-202. Urine concentrations of BIA 3-270 were below the limit of quantification. In group 8, the rate and extent of systemic availability (t(max), AUC and C(max)) of BIA 3-202 and BIA 3-270 after a high-fat meal were similar to those under fasting conditions. Inhibition of COMT activity in erythrocytes reached maximum levels at 2-2.5h post dose, with sustained inhibition up to approximately 4-6 hours, returning to baseline by about 16 hours.
  
  
  CONCLUSIONS
  BIA 3-202 was well tolerated at single 10-800mg oral doses and presented dose-proportional kinetics. It effectively inhibited COMT activity and the presence of food did not affect its pharmacokinetics or COMT inhibitory activity. The results provide a basis for further clinical studies with BIA 3-202.
authors.affiliation: Department of Research and Development, BIAL, S. Mamede do Coronado, Portugal.
authors.forename: Luis
authors.initials: L
authors.lastname: Almeida
authors.forename: Patrício
authors.initials: P
authors.lastname: Soares-da-Silva
mesh_terms: D000098:Acetophenones / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000652:urine; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D065098:Catechol O-Methyltransferase Inhibitors; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000652:urine; D006207:Half-Life; D006801:Humans; D013997:Time Factors
chemical_list: D000098:Acetophenones; D065098:Catechol O-Methyltransferase Inhibitors; D004791:Enzyme Inhibitors; C433466:nebicapone