Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Korea.
Clin Ther. 2012 Feb;34(2):305-13. doi: 10.1016/j.clinthera.2012.01.008. Epub 2012 Jan 26.
Anastrozole is an aromatase inhibitor used to treat advanced breast cancer in postmenopausal women. A generic 1-mg tablet of anastrozole was recently developed.
The study was designed to provide data to submit to Korean regulatory authorities to allow marketing of the test formulation. We evaluated the comparative bioavailability and tolerability of the test and reference formulations in healthy male adult volunteers.
This single-dose, randomized, double-blind, 2-way crossover trial was conducted in the Clinical Trial Center at the Asan Medical Center (Seoul, Korea). A total of 24 healthy male Korean volunteers were enrolled. Subjects were randomized to receive 1 mg of the test or reference formulation, and pharmacokinetic (PK) parameters were measured. After a 3-week washout period, the other formulation was administered, and PK parameters were measured again. C(max) and AUC(last) were determined from blood samples obtained at 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, and 216 hours after drug administration. The formulations were considered bioequivalent if the 90% CIs of the geometric mean ratios of test-to-reference formulations for AUC(last) and C(max) were within the bioequivalence limits of 0.8 to 1.25. Nonlinear mixed-effect modeling and Monte Carlo simulations for both formulations were also conducted, and the results were used to characterize and compare the PK properties. Safety profile and tolerability were assessed using measurements of vital signs, clinical chemistry tests, and interviews.
All enrolled subjects completed the study. A total of 8 adverse events (AEs) were reported (2 on test formulation, 6 on reference formulation) in 7 of 24 participants. These AEs were headache (n = 1), hordeolum (n = 1), and abnormal laboratory test values (n = 6). Both formulations were well tolerated, and there were no serious AEs. Both formulations were best described by a 2-compartment disposition model with lag phase. The 90% CIs of the geometric mean ratios of test formulation to reference formulation were 0.96 to 1.08 for C(max) and 0.93 to 1.0 for AUC(last).
The test and reference formulations had similar PK parameters and similar plasma concentration-time profiles. The test formulation of anastrozole met the Korean regulatory criteria (AUC and C(max)) for assuming bioequivalence. ClinicalTrials.gov identifier: NCT01105299.
阿那曲唑是一种芳香化酶抑制剂，用于治疗绝经后妇女的晚期乳腺癌。最近开发了一种通用的 1 毫克阿那曲唑片剂。
该研究旨在提供数据提交给韩国监管机构，以允许测试制剂上市。我们评估了健康成年男性志愿者中测试和参考制剂的比较生物利用度和耐受性。
这是一项单剂量、随机、双盲、2 向交叉试验，在首尔 Asan 医疗中心（韩国）的临床试验中心进行。共纳入 24 名健康的韩国男性志愿者。受试者随机接受 1 毫克测试或参考制剂，并测量药代动力学（PK）参数。在 3 周洗脱期后，再次给予另一种制剂，并再次测量 PK 参数。从给药后 0.33、0.67、1、1.5、2、3、4、6、8、12、24、48、72、96、120、168 和 216 小时的血样中确定 C(max)和 AUC(last)。如果测试-参考制剂的 AUC(last)和 C(max)的几何均数比值的 90%置信区间（CI）在 0.8 至 1.25 的生物等效性范围内，则认为制剂具有生物等效性。还对两种制剂进行了非线性混合效应模型和蒙特卡罗模拟，并使用这些结果对 PK 特性进行了表征和比较。使用生命体征、临床化学测试和访谈来评估安全性概况和耐受性。
所有入组的受试者均完成了研究。共有 8 名受试者（2 名在测试制剂组，6 名在参考制剂组）报告了 8 起不良事件（AE）。这些不良事件为头痛（n = 1）、麦粒肿（n = 1）和异常实验室检查值（n = 6）。两种制剂均耐受良好，无严重不良事件。两种制剂均通过具有滞后相的 2 隔室分布模型得到最佳描述。测试制剂与参比制剂的 C(max)几何均数比值的 90%CI 为 0.96 至 1.08，AUC(last)的几何均数比值的 90%CI 为 0.93 至 1.0。
测试和参比制剂具有相似的 PK 参数和相似的血浆浓度-时间曲线。阿那曲唑的测试制剂符合韩国监管标准（AUC 和 C(max)），可假定生物等效性。临床试验.gov 标识符：NCT01105299。
