title: Pharmacokinetic-pharmacodynamic interaction between BIA 3-202, a novel COMT inhibitor, and levodopa/carbidopa.
abstract: This study investigated the tolerability and the pharmacokinetic and pharmacodynamic interactions between single oral administration of BIA 3-202 (50 mg, 100 mg, 200 mg, and 400 mg), a novel catechol-O-methyltransferase (COMT) inhibitor, and standard carbidopa/levodopa 25 mg/100 mg (Sinemet 25/100) in healthy adult volunteers. This was a single-center, double-blind, placebo-controlled, randomized, crossover study with 5 single-dose treatment periods with a washout period of 2 weeks between doses. During each treatment period, a different dose of BIA 3-202 or placebo was administered concomitantly with Sinemet 25/100. Tolerability was assessed by recording adverse events, vital signs, continuous EKG, and clinical laboratory parameters. Pharmacokinetic parameters of levodopa and 3-O-methyl-levodopa (3-OMD) were determined. The activity of soluble COMT in erythrocytes was also measured. Eighteen subjects (10 men and 8 women) participated in the study. The drug combination was well tolerated, with the adverse events reported being transient and generally mild in severity. Mean levodopa Cmax values were attained at 0.8 to 1.8 hours postdose. Thereafter, plasma levodopa levels declined with a mean t1/2 that increased in a manner that depended on the dose of BIA 3-202. The increase in systemic exposure to levodopa (AUC0-infinity) occurred at all doses of BIA 3-202, attaining its maximum at 200 mg BIA 3-202 (95% conficence interval, 1.43-1.73). The mean Cmax and AUC0-infinity values of 3-OMD decreased dose proportionally in BIA 3-202-treated subjects, with differences being statistically significant for all the doses tested. Maximum COMT inhibition occurred between 0.8 and 2.0 hours postdose, and ranged from 56 (50 mg) to 85% (400 mg). Time to return to baseline COMT activity ranged from 6 (50 mg) to 18 hours (400 mg), following the same dose-dependent tendency. In conclusion, the novel COMT inhibitor BIA 3-202 increased the bioavailability of levodopa and reduced the formation of 3-OMD when administered with standard levodopa/carbidopa.
authors.affiliation: Department of Research and Development, BIAL, S Mamede do Coronado, Portugal.
authors.forename: Luis
authors.initials: L
authors.lastname: Almeida
authors.forename: Manuel
authors.initials: M
authors.lastname: Vaz-da-Silva
authors.forename: Pedro
authors.initials: P
authors.lastname: Silveira
authors.forename: Amilcar
authors.initials: A
authors.lastname: Falcão
authors.forename: Joana
authors.initials: J
authors.lastname: Maia
authors.forename: Ana
authors.initials: A
authors.lastname: Loureiro
authors.forename: Leonel
authors.initials: L
authors.lastname: Torrão
authors.forename: Rita
authors.initials: R
authors.lastname: Machado
authors.forename: Lyndon
authors.initials: L
authors.lastname: Wright
authors.forename: Patrício
authors.initials: P
authors.lastname: Soares-da-Silva
mesh_terms: D000098:Acetophenones / Q000493:pharmacokinetics*; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D002230:Carbidopa / Q000493:pharmacokinetics* / Q000494:pharmacology; D002394:Catechol O-Methyltransferase / Q000097:blood; D065098:Catechol O-Methyltransferase Inhibitors; D018592:Cross-Over Studies; D015259:Dopamine Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D018491:Dopamine Agonists / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004338:Drug Combinations; D004347:Drug Interactions; D004361:Drug Tolerance; D004912:Erythrocytes / Q000187:drug effects; D005260:Female; D006207:Half-Life; D006801:Humans; D007980:Levodopa / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D013997:Time Factors
chemical_list: D000098:Acetophenones; D065098:Catechol O-Methyltransferase Inhibitors; D015259:Dopamine Agents; D018491:Dopamine Agonists; D004338:Drug Combinations; C009265:carbidopa, levodopa drug combination; D007980:Levodopa; D002394:Catechol O-Methyltransferase; D002230:Carbidopa; C433466:nebicapone