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 (Cmax) of BIA 3-202 were attained at 0.522.5h (tmax) and thereafter declined with an apparent terminal half-life (t1/2) of 1.52–5h. Over the dose range of 102800mg, 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, AUC0-t increased in the ratio 1:5. In most subjects, the tmax of BIA 3-270 was attained at the last sampling time and, therefore, t1/2 could not be estimated. Urine assays showed that less than 1% of the total dose admi nistered 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 (tmax, AUC and Cmax) 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.
Conclusion: 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.
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The study was funded by Bial (Portela & Ca SA), S. Mamede do Coronado, Portugal.
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Almeida, L., Soares-da-Silva, P. Pharmacokinetics and Pharmacodynamics of BIA 3-202, a Novel COMT Inhibitor, during First Administration to Humans. Drugs R&D 4, 207–217 (2003). https://doi.org/10.2165/00126839-200304040-00001
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DOI: https://doi.org/10.2165/00126839-200304040-00001