Pharmacokinetic and Pharmacodynamic Profiles of BIA 3–202, a Novel Catechol‐O‐Methyltransferase (COMT) Inhibitor, during Multiple‐Dose Administration to Healthy Subjects

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Abstract
The tolerability, pharmacodynamics, and pharmacokinetics of BIA 3–202 (50 mg, 100 mg, and 200 mg twice daily and 200 mg thrice daily), a novel catechol‐O‐methyltransferase (COMT) inhibitor, were investigated in healthy volunteers. BIA 3–202 was administered to four sequential groups of 8 healthy male subjects under a double‐blind, randomized, placebo‐controlled design. Within each group, 2 subjects were randomized to treatment with placebo. Treatment duration was 9 days: single dose on the first and last days and twice or thrice daily on days 3 to 8. BIA 3–202 was well tolerated at all dose regimens tested. Median maximum plasma BIA 3–202 concentrations were attained at 0.5 to 2.5 hours postdose. Thereafter, concentrations declined with a t1/2 of approximately 2 to 4 hours. The increase in the extent of systemic exposure, as measured by AUC0‐τ was approximately proportional to the administered dose. Steady state of plasma BIA 3–202 concentrations occurred by day 4 in all dose groups. Less than 1% of the total dose administered was excreted in urine up to 48 hours postdose. BIA 3–202 markedly reduced soluble COMT (S‐COMT) activity in erythrocytes, with maximum inhibition occurring at 1 to 2 hours postdose; enzyme activity returned to baseline levels by approximately 8 hours. Inhibition of S‐COMT activity appeared to increase with increasing doses of BIA 3–202 on both day 1 and day 9. In conclusion, BIA 3–202 was well tolerated in all the oral multiple‐dose regimens tested. BIA 3–202 was shown to inhibit S‐COMT activity in erythrocytes, and its pharmacokinetics appeared to be linear (i.e., dose independent and time invariant).