Elkoshi Zeev, Behr Dan, Mirimsky Alex, Tsvetkov Igor, Danon Abraham
Teva Pharmaceutical Industries, POB 353, Kfar-Sava, 44102, Israel.
AstraZeneca, Mölndal, Sweden.
Clin Drug Investig. 2002 Sep;22(9):585-592. doi: 10.2165/00044011-200222090-00003.
To evaluate the bioequivalence of two enteric-coated formulations of omeprazole, Losec® (reference) and Omepradex® (test). It is hypothesised that formulation differences may be accentuated following multiple-dose administration, and that testing after multiple administration may therefore provide a more sensitive assessment of bioequivalence.
The study comprised two parts: an in vitro dissolution test and an in vivo bioavailability study. The latter was a randomised, two-way crossover comparative study after a single dose and after multiple doses in healthy volunteers. Forty subjects were randomly allocated to receive either test or reference product, once daily in the morning, and blood samples were taken on days 1 and 5. Standard pharmacokinetic analyses were performed, and analysis of variance (ANOVA) was used to compare the log-transformed variables in a model including terms for treatment, subject and period.
Although both products meet the formal requirements specified by the United States Pharmacopoeia (USP) for enteric-coated articles, the in vitro dissolution experiments revealed widely differing properties for the two tested products. Less than 10% of the drug content was recovered from the Omepradex® formulation following a pre-exposure to pH 3 or 4, compared with over 90% recovered from the Losec® formulation. These findings were in agreement with the results of the in vivo bioavailability study, which showed that the two products differed in both their rate and extent of absorption after a single dose and following multiple doses. The products failed the bioequivalence test for area under the plasma concentration-time curve (AUC) and maximum plasma drug concentration (C) after a single dose [AUC: test/reference ratio 0.85, 90% confidence interval (0.76-0.95); C: test/reference ratio 0.85, 90% confidence interval (0.75-0.95)], and the difference between the formulations was even more pronounced after multiple doses [AUC: test/reference ratio 0.73, 90% confidence interval (0.65-0.83); Cmax: test/reference ratio 0.71, 90% confidence interval (0.63-0.81)].
These data suggest that bioequivalence studies on enteric-coated proton pump inhibitors should include both single- and multiple-dose elements to be fully decisive. The two omeprazole products failed to show bioequivalence, with the observed differences being even more apparent after multiple doses, as postulated. Based on this study, the two products may not be considered either therapeutically equivalent or interchangeable.
评估两种奥美拉唑肠溶制剂（洛赛克®（参比制剂）和奥美普明®（受试制剂））的生物等效性。据推测，多剂量给药后制剂差异可能会更加明显，因此多次给药后进行测试可能会对生物等效性提供更敏感的评估。
该研究包括两个部分：体外溶出度试验和体内生物利用度研究。后者是一项在健康志愿者中进行的单剂量和多剂量给药后的随机、双向交叉对比研究。40名受试者被随机分配接受受试产品或参比产品，每天早晨服用一次，并在第1天和第5天采集血样。进行标准药代动力学分析，并使用方差分析（ANOVA）在一个包含治疗、受试者和周期项的模型中比较对数转换后的变量。
尽管两种产品均符合美国药典（USP）对肠溶制剂规定的正式要求，但体外溶出度实验显示两种受试产品特性差异很大。在预先暴露于pH 3或4后，奥美普明®制剂中回收的药物含量不到10%，而洛赛克®制剂中回收的药物含量超过90%。这些发现与体内生物利用度研究结果一致，该研究表明两种产品在单剂量和多剂量给药后的吸收速率和程度均存在差异。单剂量给药后血浆浓度-时间曲线下面积（AUC）和最大血浆药物浓度（Cmax）的生物等效性测试中产品未通过 [AUC：受试/参比比值0.85，90%置信区间（0.76 - 0.95）；Cmax：受试/参比比值0.85，90%置信区间（0.75 - 0.95）]，多剂量给药后制剂之间的差异更为明显 [AUC：受试/参比比值0.73，90%置信区间（0.65 - 0.83）；Cmax：受试/参比比值0.71，90%置信区间（0.63 - 0.81）]。
这些数据表明，对肠溶质子泵抑制剂的生物等效性研究应同时包括单剂量和多剂量要素，才能做出全面的判定。两种奥美拉唑产品未显示生物等效性，观察到的差异在多剂量给药后更加明显，正如所假设的那样。基于本研究，这两种产品在治疗上可能既不等效也不可互换。
