Pharmacokinetic and pharmacodynamic profiles of BIA 3-202, a novel catechol-O-methyltransferase (COMT) inhibitor, during multiple-dose administration to healthy subjects

被引:17
作者
Almeida, L [1 ]
Soares-Da-Silva, P [1 ]
机构
[1] BIAL, Dept Res & Dev, P-4745457 Sao Mamede do Coronado, Portugal
关键词
catechol-O-methyltransferase; levodopa; Parkinson's disease; pharmacokinetics; pharmacodynamics;
D O I
10.1177/0091270003258666
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 t(1/2) of approximately 2 to 4 hours. The increase in the extent of Systemic exposure, as measured by AUC(0-tau), 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-GOMT 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).
引用
收藏
页码:1350 / 1360
页数:11
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