Marzo A, Monti N, Ripamonti M, Marzo P, Wool C, Cerutti R, Maggi G C
Real s.r.l., Laboratory of Pharmacokinetics and Drug Metabolism, Como, Italy.
Arzneimittelforschung. 1997 Apr;47(4):385-9.
The S-naproxen betainate sodium salt monohydrate (naproxen-betaNa, CAS 104124-26-7, Aprenin, test drug), and the sodium salt of S-naproxen (reference), were administered to twelve healthy volunteers of both sexes according to a crossover design, in a single dose of one 575 mg capsule of test, containing 342 mg of S-naproxen and two 275 mg tablets of reference, containing 502 mg of S-naproxen. Blood samples were drawn off over a 24-h period before (time 0) and after administration at foreseen time intervals. Naproxen was measured in plasma by a validated HPLC assay with UV detection which was able to detect 1 microgram/ml and proved to be linear in the range 1-100 micrograms/ml. The non-compartmental pharmacokinetic parameters obtained were statistically processed according to the EU guidance note on bioavailability and bioequivalence Cmax, AUC0-24h and AUC0-infinity were normalized to the dose of 502 mg of naproxen and log-transformed before statistical analysis to assess bioequivalence. Dose-normalized values of plasma concentrations encountered with the two formulations proved to overlap, with the exception of the first sampling time which showed naproxen concentrations that were higher with test drug than with reference. The specific test for bioequivalence led to 90% confidence intervals within the 80-125% range with target pharmacokinetic parameters, whereas the time to peak (tmax) observed with the test and reference drugs did not differ to any statistically significant degree when analysed with Wilcoxon's non-parametric test. It is concluded that the test drug should be declared bioequivalent with the reference drug in terms of dose-normalized concentrations, despite the more rapid increase in plasma concentrations of naproxen observed at the first sampling time with test drug.
将S-萘普生甜菜碱钠盐一水合物（萘普生-βNa，化学物质登记号104124-26-7，Aprenin，试验药物）和S-萘普生钠盐（参比制剂），按照交叉设计给予12名男女健康志愿者，单次服用1粒575 mg的试验胶囊，其中含342 mg S-萘普生，以及2片275 mg的参比制剂片剂，其中含502 mg S-萘普生。在给药前（0时）及给药后按预定时间间隔在24小时内采集血样。采用经过验证的配有紫外检测的高效液相色谱法测定血浆中的萘普生，该方法能够检测到1微克/毫升，并且在1-100微克/毫升范围内呈线性。根据欧盟关于生物利用度和生物等效性的指导说明，对所获得的非房室药代动力学参数进行统计处理。将Cmax、AUC0-24h和AUC0-∞归一化为502 mg萘普生的剂量，并在统计分析前进行对数转换，以评估生物等效性。两种制剂的血浆浓度剂量归一化值被证明相互重叠，但第一个采样时间除外，此时试验药物的萘普生浓度高于参比制剂。生物等效性的具体试验得出，目标药代动力学参数的90%置信区间在80-125%范围内，而采用威尔科克森非参数检验分析时，试验药物和参比药物的达峰时间（tmax）在任何统计学显著程度上均无差异。得出的结论是，尽管在第一个采样时间观察到试验药物的萘普生血浆浓度升高更快，但就剂量归一化浓度而言，试验药物应被声明与参比药物生物等效。
