title: The effect of tolcapone on levodopa pharmacokinetics is independent of levodopa/carbidopa formulation.
abstract: Clinical pharmacology studies have shown that the catechol-O-methyltransferase inhibitor tolcapone increases the bioavailability area under the plasma concentration-time curve (AUC) and the plasma elimination half-life (t1/2) of levodopa. The objective of the study was to evaluate the pharmacokinetics of levodopa and 3-O-methyldopa (3-OMD) after coadministration of tolcapone 200 mg with levodopa/ carbidopa in the following doses: 100/10 mg, 100/25 mg, 200/20 mg, 200/50 mg, 250/25 mg (all immediate-release) and 200/50 mg (controlled-release). Thirty healthy male volunteers were divided into four groups: three groups of 8 and one group of 6. Participants in the first three groups received two formulations of levodopa/carbidopa. Each dose was administered on two occasions, once with tolcapone 200 mg and once with placebo (four-way crossover). In the fourth group, one formulation was given on two occasions, once with tolcapone 200 mg and once with placebo (two-way crossover). Dosing days were separated by a 7-day washout. The effect of tolcapone on levodopa and 3-OMD pharmacokinetics was found to be similar with all levodopa/carbidopa formulations. The absorption of levodopa was unaffected by tolcapone in all treatment groups and the maximum plasma concentration (Cmax) remained unchanged. When tolcapone was given with the immediate-release formulations, levodopa AUC increased by 60-90% and levodopa t1/2 by 20-60%. With tolcapone and the controlled-release formulation, AUC increased by 80% and t1/2 by 60%. With all levodopa/carbidopa formulations, 3-OMD Cmax decreased by 80% and AUC by 70% with tolcapone. The tolerability of all treatment combinations was similar. We conclude that adjunctive treatment with tolcapone should have similar levodopa-potentiating clinical effects, regardless of the levodopa/carbidopa formulation.
authors.affiliation: Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd., Basel, Switzerland. karin.jorga@roche.com
authors.forename: K
authors.initials: K
authors.lastname: Jorga
authors.forename: B
authors.initials: B
authors.lastname: Fotteler
authors.forename: G
authors.initials: G
authors.lastname: Sedek
authors.forename: T
authors.initials: T
authors.lastname: Nielsen
authors.forename: J
authors.initials: J
authors.lastname: Aitken
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001577:Benzophenones / Q000008:administration & dosage / Q000494:pharmacology*; D001682:Biological Availability; D002230:Carbidopa / Q000008:administration & dosage*; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D007980:Levodopa / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D009596:Nitrophenols; D010300:Parkinson Disease / Q000188:drug therapy*; D000077867:Tolcapone
chemical_list: D000978:Antiparkinson Agents; D001577:Benzophenones; D003692:Delayed-Action Preparations; D009596:Nitrophenols; D007980:Levodopa; D000077867:Tolcapone; D002230:Carbidopa