title: COMT inhibition by tolcapone further improves levodopa pharmacokinetics when combined with a dual-release formulation of levodopa/benserazide. A novel principle in the treatment of Parkinson's disease.
abstract: The objective of the study reported here was the investigation of the effect of catechol-O-methyl transferase (COMT) inhibition by tolcapone on the pharmacokinetics of levodopa and 3-O-methyldopa (3-OMD) after administration of a new dual-release formulation (dual-RF) of levodopa/benserazide (200/50). The study had a double-blind, placebo-controlled, randomized, crossover design and was conducted in 18 healthy young subjects. On the 2 treatment days, separated by a washout period of 7 days, the dual-RF was administered in combination (blinded) with tolcapone (200 mg) or placebo. Both treatment combinations were well tolerated. Tolcapone increased the bioavailability (AUC 0-infinity) and apparent elimination half-life (t(1/2)) of levodopa by 80 and 40%, respectively, compared to placebo. The maximal plasma concentration (Cmax) was slightly elevated by tolcapone. In the presence of tolcapone, formation of 3-OMD was substantially reduced. In conclusion, the effect of tolcapone on levodopa pharmacokinetics after administration of the dual-RF is similar to the one observed after immediate- and slow-RFs and leads to a marked improvement in levodopa pharmacokinetics and subsequently to an optimization of levodopa therapy.
authors.affiliation: Department of Clinical Research, Roche Pharma (Schweiz) AG, Reinach, Switzerland.urs. gasser@roche.com
authors.forename: U E
authors.initials: UE
authors.lastname: Gasser
authors.forename: K
authors.initials: K
authors.lastname: Jorga
authors.forename: C
authors.initials: C
authors.lastname: Crevoisier
authors.forename: S E
authors.initials: SE
authors.lastname: Hovens
authors.forename: P L
authors.initials: PL
authors.lastname: van Giersbergen
mesh_terms: D000293:Adolescent; D000328:Adult; D000978:Antiparkinson Agents / Q000097:blood / Q000378:metabolism* / Q000627:therapeutic use; D001545:Benserazide / Q000097:blood / Q000378:metabolism* / Q000627:therapeutic use; D001577:Benzophenones / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D002394:Catechol O-Methyltransferase / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007980:Levodopa / Q000097:blood / Q000378:metabolism* / Q000627:therapeutic use; D008297:Male; D009596:Nitrophenols; D010300:Parkinson Disease / Q000188:drug therapy / Q000201:enzymology*; D013997:Time Factors; D000077867:Tolcapone
chemical_list: D000978:Antiparkinson Agents; D001577:Benzophenones; D009596:Nitrophenols; D007980:Levodopa; D001545:Benserazide; D000077867:Tolcapone; D002394:Catechol O-Methyltransferase