title: Comparative single- and multiple-dose pharmacokinetics of levodopa and 3-O-methyldopa following a new dual-release and a conventional slow-release formulation of levodopa and benserazide in healthy volunteers.
abstract: The objective was to assess the single- and multiple-dose pharmacokinetics of levodopa and 3-O-methyldopa following administration of a new dual-release and conventional slow-release formulation of levodopa/benserazide in the dose ratio of 4:1. In an open-label, two-way cross-over study, 20 healthy volunteers were randomized to receive first either Madopar DR or Madopar HBS for 8 days. Then they crossed over to the other formulation. A first dose of 200 mg levodopa and 50 mg benserazide ('250' mg) was given on day 1, '125' mg t.i.d. on the subsequent 6 days (days 2-7), followed by '250' mg on day 8. The two treatment periods of 8 days were separated by a wash-out period of at least 7 days. Blood samples were taken at specific times over a 12-hour period (day 1) or a 36-hour period (day 8). Plasma concentrations of levodopa and 3-O-methyldopa were measured by high-performance liquid chromatography for pharmacokinetic evaluation. The pharmacokinetics of levodopa after a single-dose administration (day 1) of Madopar DR and Madopar HBS were significantly different as reflected by the respective mean values of maximum plasma concentration (C(max) 1.99 vs. 0.82 mg x l-1), time to reach maximum concentration (t(max) 0.7 vs. 2.6 h) and area under the plasma concentration-time curve (AUC(0- infinity ) 4.52 vs. 3.18 mg x h x l-1). The respective values after multiple doses (day 8) were: C(max) 1.98 vs. 0.93 mg x l-1, t(max) 0.7 vs. 2.3 h and AUC(0-infinity ) 4.84 vs. 3.96 mg x h x l-1. The relative bioavailability (Madopar DR vs. Madopar HBS) was 1.73 on day 1 and 1.32 on day 8. Bioequivalence could not be demonstrated for log-transformed data of AUC and C(max) within a predefined range of 80-125 and 70-143%, respectively. In conclusion, the observed differences in C(max), t(max) and AUC are consistent with a faster rate and higher extent of levodopa absorption after administration of Madopar DR. Statistical evaluation of these kinetic data showed that Madopar DR is not bioequivalent to Madopar HBS.
authors.affiliation: Clinical Pharmacology Services, Dornach, Switzerland. ch.crevoisier@intergga.ch
authors.forename: C
authors.initials: C
authors.lastname: Crevoisier
authors.forename: A
authors.initials: A
authors.lastname: Monreal
authors.forename: B
authors.initials: B
authors.lastname: Metzger
authors.forename: T
authors.initials: T
authors.lastname: Nilsen
mesh_terms: D000328:Adult; D000978:Antiparkinson Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001545:Benserazide / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D015259:Dopamine Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007980:Levodopa / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008297:Male; D008750:Methyldopa / Q000493:pharmacokinetics*; D012016:Reference Values
chemical_list: D000978:Antiparkinson Agents; D003692:Delayed-Action Preparations; D015259:Dopamine Agents; D004338:Drug Combinations; C005177:benserazide, levodopa drug combination; D007980:Levodopa; D008750:Methyldopa; D001545:Benserazide