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

The objective was to assess the single- and multipledose pharmacokinetics of levodopa and 3-O-methyidopa following administration of a new dual-release and conventional slow-release formulation of levoclopa/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(R) DR or Maclopar(R) HBS for 8 days. Then they crossed over to the other formulation. A first dose of 200 mg levoclopa and 50 mg benserazide ('250'mg) was given on day 1,'125'mgt.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.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.h.l(-1)). The respective values after multiple doses (day 8) were: C-max 1.98 vs. 0.93 mg.l(-1), t(max) 0.7 vs. 2.3 h and AUC(0-infinity) 4.84 vs. 3.96 mg.h.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 levoclopa absorption after administration of Madopar DR. Statistical evaluation of these kinetic data showed that Madopar DR is not bioequivalent to Madopar HBS.