Medical Department, Grupo Tecnimede, Sociedade Tecnico-Medicinal S.A., Sintra, Portugal.
Clin Ther. 2010 Mar;32(3):556-74. doi: 10.1016/j.clinthera.2010.03.008.
Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is an immunosuppressive agent indicated for the prophylaxis of organ rejection in allogeneic kidney, heart, or liver transplant recipients. The European regulatory authorities require bioequivalence studies for the marketing of generic products.
The aim of this study was to assess the bioequivalence of a generic (test) and branded (reference) formulation of MMF 500 mg and MPA.
This single-center, single-dose, randomized, open-label, 4-way crossover study was conducted at Anapharm's Clinical Research Facility, Québec, Québec, Canada. Healthy volunteers aged 18 to 55 years were eligible. Subjects were assigned to receive, in randomized order, a single dose of the test and reference formulations of MMF 500 mg under fasting conditions. Because the study design was 4-way replicate, there were 2 test periods and 2 reference periods. The 4 study periods were each separated by a 14-day washout period. Blood samples were collected over a period of 12 hours after administration for the determination of MMF pharmacokinetic properties, and over 48 (+/-0.5) hours, for MPA properties. Concentrations of the analytes were determined by reverse LC and detected using LC-MS/MS. Pharmacokinetic parameters were calculated from MMF and MPA concentration data using noncompartmental analysis. C(max) and AUC(0-t) were the primary evaluation criteria, while AUC(0-infinity) was a secondary parameter. The drugs were to be considered bioequivalent if the 90% CIs for the test/reference ratios of natural logarithm-transformed values of these parameters (obtained using ANOVA) were between 80% and 125%, per European regulations for bioequivalence. Tolerability was monitored using physical examination, including vital sign measurements, laboratory analysis, and adverse-events (AE) monitoring (including patient interview).
A total of 103 subjects were enrolled (64 men, 39 women; 101 white, 2 black; mean [SD] age, 38 [10] years; weight, 68.2 [9.1] kg). The 90% CIs were as follows: MMF, C(max), 85.94% to 106.63%; AUC(0-t), 91.94% to 102.20%; and AUC(0-infinity), 93.15% to 105.48%; MPA, C(max), 92.03% to 105.82%; AUC(0-t), 97.42% to 100.59%; and AUC(0-infinity), 96.96% to 100.90%. These values met with the regulatory definition of bioequivalence. A total of 148 AEs were reported (68 in subjects who received the test treatment and 80 in subjects who received the reference treatment). The most commonly reported AEs were procedural pain (13/102 [12.7%] and 10/101 [9.9%] with the test and reference formulations, respectively), procedural site reaction (12 [11.8%] and 4 [4.0%]), and somnolence (7 [6.9%] and 14 [13.9%]).
The generic and branded formulations of MMF 500 mg met the European regulatory criteria for assuming bioequivalence, based on the rate and extent of absorption of a single dose under fasting conditions. Both formulations were well tolerated in these healthy volunteers.
霉酚酸酯（MMF），霉酚酸（MPA）的前体药物，是一种免疫抑制剂，用于预防同种异体肾、心或肝移植受者的器官排斥反应。欧洲监管机构要求对仿制药进行生物等效性研究，方可上市销售。
本研究旨在评估一种 MMF 500mg 通用（测试）和品牌（参比）制剂的生物等效性。
这是一项在加拿大魁北克省魁北克市 Anapharm 临床研究设施进行的单中心、单次、随机、开放标签、四交叉研究。年龄在 18 至 55 岁之间的健康志愿者符合入选条件。受试者按照随机顺序，分别空腹接受单剂量测试和参比制剂的 MMF 500mg。由于研究设计为四交叉重复，因此有 2 个测试期和 2 个参比期。4 个研究期之间各间隔 14 天洗脱期。给药后 12 小时内采集血样，以确定 MMF 的药代动力学特性，48（+/-0.5）小时内采集血样，以确定 MPA 的特性。分析物的浓度通过反相 LC 和 LC-MS/MS 检测来确定。采用非房室分析方法从 MMF 和 MPA 浓度数据中计算药代动力学参数。C(max)和 AUC(0-t)是主要评价标准，而 AUC(0-infinity)是次要参数。根据欧洲生物等效性法规，如果这些参数的自然对数转换值的测试/参比值（通过方差分析获得）的 90%置信区间（CI）在 80%和 125%之间，则认为药物具有生物等效性。通过体格检查、包括生命体征测量、实验室分析和不良事件（AE）监测（包括患者访谈）来监测耐受性。
共有 103 名受试者入组（64 名男性，39 名女性；101 名白种人，2 名黑种人；平均[标准差]年龄 38[10]岁；体重 68.2[9.1]kg）。90%CI 如下：MMF，C(max)，85.94%至 106.63%；AUC(0-t)，91.94%至 102.20%；AUC(0-infinity)，93.15%至 105.48%；MPA，C(max)，92.03%至 105.82%；AUC(0-t)，97.42%至 100.59%；AUC(0-infinity)，96.96%至 100.90%。这些值符合生物等效性的监管定义。共报告了 148 例不良事件（在接受测试治疗的受试者中为 68 例，在接受参比治疗的受试者中为 80 例）。最常见的不良事件是程序性疼痛（分别为 13/102[12.7%]和 10/101[9.9%]，与测试和参比制剂有关）、程序性部位反应（12[11.8%]和 4[4.0%]）和嗜睡（7[6.9%]和 14[13.9%]）。
基于禁食条件下单次给药的吸收速度和程度，MMF 500mg 的通用和品牌制剂均符合欧洲监管标准，可假定具有生物等效性。这两种制剂在这些健康志愿者中均具有良好的耐受性。
