Crevoisier C, Monreal A, Metzger B, Nilsen T
Clinical Pharmacology Services, Dornach, Switzerland.
Eur Neurol. 2003;49(1):39-44. doi: 10.1159/000067025.
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.
目的是评估左旋多巴与3 - O - 甲基多巴在以4:1剂量比例给予左旋多巴/苄丝肼的新型双释放和传统缓释制剂后的单剂量和多剂量药代动力学。在一项开放标签、双向交叉研究中，20名健康志愿者被随机分组，首先接受美多芭双释放片（Madopar DR）或美多芭缓释片（Madopar HBS）治疗8天。然后他们交叉接受另一种制剂。第1天给予首剂200 mg左旋多巴和50 mg苄丝肼（“250”mg），随后6天（第2 - 7天）每天3次给予“125”mg，第8天给予“250”mg。两个为期8天的治疗周期之间有至少7天的洗脱期。在12小时（第1天）或36小时（第8天）的特定时间采集血样。通过高效液相色谱法测定左旋多巴和3 - O - 甲基多巴的血浆浓度以进行药代动力学评估。单剂量给药（第1天）后，美多芭双释放片和美多芭缓释片的左旋多巴药代动力学有显著差异，分别由最大血浆浓度（C(max) 1.99对0.82 mg·L⁻¹）、达到最大浓度的时间（t(max) 0.7对2.6小时）以及血浆浓度 - 时间曲线下面积（AUC(0 - ∞) 4.52对3.18 mg·h·L⁻¹）的各自平均值反映。多剂量给药（第8天）后的相应值为：C(max) 1.98对0.93 mg·L⁻¹，t(max) 0.7对2.3小时，AUC(0 - ∞) 4.84对3.96 mg·h·L⁻¹。第1天的相对生物利用度（美多芭双释放片对比美多芭缓释片）为1.73，第8天为1.32。对于AUC和C(max)的对数转换数据，在分别为80 - 125%和70 - 143%的预定义范围内，无法证明生物等效性。总之，观察到的C(max)、t(max)和AUC的差异与美多芭双释放片给药后左旋多巴吸收更快的速率和更高的程度一致。对这些动力学数据的统计评估表明，美多芭双释放片与美多芭缓释片不等效。
