Pharmacokinetics and Bioequivalence Evaluation of Two Different Atorvastatin Calcium 10-mg Tablets: A Single-Dose, Randomized-Sequence, Open-Label, Two-Period Crossover Study in Healthy Fasted Chinese Adult Males
Pharmacokinetics and Bioequivalence Evaluation of Two Different Atorvastatin Calcium 10-mg Tablets: A Single-Dose, Randomized-Sequence, Open-Label, Two-Period Crossover Study in Healthy Fasted Chinese Adult Males
复制标题
DOI：
10.1016/j.clinthera.2010.07.004
复制
发表时间：
2010-07-01
影响因子：
3.2
通讯作者：
Yu, Chen
中科院分区：
文献类型：
--
作者：
Liu, Yan-Mei;Pu, Hua-Hua;Yu, Chen
背景资料：阿托伐他汀钙是一种3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，适用于预防心血管疾病和治疗血脂异常。目前缺乏阿托伐他汀在中国人群中的药代动力学信息，并且法规要求在中国上市仿制药必须进行生物等效性研究。目的：本研究的目的是评估阿托伐他汀钙10 mg片剂试验制剂和品牌参比制剂在健康空腹中国男性志愿者中的药代动力学和生物等效性。方法：这是一项单次给药、随机序列、开放标签、2阶段交叉研究，两次给药之间有2周洗脱期。健康中国男性被随机分配接受20 mg试验制剂或参比制剂，在48小时间隔内采集13份血样。采用经验证的液相色谱同位素稀释质谱法同时测定母体药物阿托伐他汀和邻羟基阿托伐他汀（主要活性代谢产物）的血浆浓度。计算药代动力学参数，包括C-max、T-max、t（1/2）、AUC（0-t）和AUC（0-无穷大）。如果阿托伐他汀AUC和C-max对数转换比值的90% CI在中国国家食品药品监督管理局确定的预定生物等效性范围内（AUC为0.80-1.25，C-max为0.70-1.43），则认为2种制剂具有生物等效性。通过生命体征监测、体格检查、12导联心电图和不良事件（AE）受试者访谈，在整个研究过程中评估耐受性。结果：共评估了66例受试者纳入研究; 20例在研究开始前被排除。在46名健康受试者中（平均[SD]年龄，24.1 [2.5]岁;身高，170.8 [5.1] cm;体重，64.6 [6.4] kg;体重指数（BMI），22.1 [1.7] kg/m（2））完成研究的45名受试者（平均[SD]年龄，24.1 [2.5]岁;身高，171.1 [4.9] cm;体重，64.8 [6.3] kg; BMI，22.1 [1.7] kg/m2）纳入药代动力学和生物等效性分析; 1例受试者被排除在这些分析之外，因为他在两个阶段错误地接受了相同的制剂。未观察到周期或序列效应。C-max、AUC（0-t）和AUC的平均值阿托伐他汀供试制剂和参比制剂（0-无穷大）（分别为8.78和10.76 ng/mL、38.22和40.02 ng/mL/h、42.73和44.51 ng/mL/h）和邻羟基阿托伐他汀（5.78和5.77 ng/mL，47.32和48.47 ng/mL/h，52.36和53.14 ng/mL/h）无显著差异。阿托伐他汀（分别为0.73-0.91、0.92-1.02和0.91-1.01）和邻羟基阿托伐他汀（0.83-1.05、0.92 - 1.02和0.93-1.02）的C-max、AUC（0-t）和AUC（0-无穷大）的自然对数转换比值的90% CI均在生物等效性验收限度内。3例受试者（6.5%）共报告了4例轻度AE（1例腹部不适和3例静脉穿刺晕厥），认为这些AE与研究药物给药无关。结论：这项单次给药（20 mg）研究发现，阿托伐他汀钙10 mg片剂的试验制剂和参比制剂符合假定这些健康空腹中国男性志愿者具有生物等效性的法规定义。两种制剂在研究人群中的耐受性通常良好。中国国家注册代码：2007 L02512。(Clin Ther. 2010;32：1396-1407）（C）2010 Excerpta Medica Inc.
Background: Atorvastatin calcium is a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor indicated for the prevention of cardiovascular disease and for the treatment of dyslipidemia. Information on the pharmacokinetics of atorvastatin in a Chinese population is lacking, and regulatory requirements necessitate a bioequivalence study for the marketing of a generic product in China.Objective: The aim of the present study was to assess the pharmacokinetics and bioequivalence of a test and branded reference formulation of atorvastatin calcium 10-mg tablets in healthy fasted Chinese male volunteers.Methods: This was a single-dose, randomized-sequence, open-label, 2-period crossover study with a 2-week washout period between doses. Healthy Chinese males were randomly assigned to receive 20 mg of either the test or reference formulation, and 13 blood samples were obtained over a 48-hour interval. Plasma concentrations of parent atorvastatin and ortho-hydroxy-atorvastatin (primary active metabolite) were simultaneously determined using a validated liquid chromatography isotopic dilution mass spectrometry method. Pharmacokinetic parameters, including C-max, T-max, t(1/2), AUC(0-t), and AUC(0-infinity), were calculated. The 2 formulations were to be considered bioequivalent if 90% CIs for the log-transformed ratios of AUC and C-max of atorvastatin were within the predetermined bioequivalence range (0.80-1.25 for AUC and 0.70-1.43 for C-max) as established by the State Food and Drug Administration of China. Tolerability was evaluated throughout the study by vital signs monitoring, physical examinations, 12-lead ECGs, and subject interviews on adverse events (AEs).Results: A total of 66 subjects were assessed for inclusion; 20 were excluded prior to study initiation. Of the 46 healthy subjects (mean [SD] age, 24.1 [2.5] years; height, 170.8 [5.1] cm; weight, 64.6 [6.4] kg; body mass index (BMI), 22.1 [1.7] kg/m(2)) who completed the study, 45 subjects (mean [SD] age, 24.1 [2.5] years; height, 171.1 [4.9] cm; weight, 64.8 [6.3] kg; BMI, 22.1 [1.7] kg/m(2)) were included in the pharmacokinetic and bioequivalence analyses; 1 subject was excluded from these analyses because he mistakenly received the same formulation in both periods. No period or sequence effect was observed. The mean values of C-max, AUC(0-t), and AUC(0-infinity) for the test and reference formulations of atorvastatin (8.78 and 10.76 ng/mL, 38.22 and 40.02 ng/mL/h, 42.73 and 44.51 ng/mL/h, respectively) and ortho-hydroxy-atorvastatin (5.78 and 5.77 ng/mL, 47.32 and 48.47 ng/mL/h, 52.36 and 53.14 ng/mL/h) were not significantly different. The 90% CIs for natural log-transformed ratios of C-max, AUC(0-t), and AUC(0-infinity) of both atorvastatin (0.73-0.91, 0.92-1.02, and 0.91-1.01, respectively) and ortho-hydroxy-atorvastatin (0.83-1.05, 0.92-1.02, and 0.93-1.02) were within the bioequivalence acceptance limits. Three subjects (6.5%) reported a total of 4 mild AEs (1 abdominal discomfort and 3 venipuncture syncope), which were not considered to be associated with administration of the study drug.Conclusions: This single-dose (20 mg) study found that the test and reference formulations of atorvastatin calcium 10-mg tablet met the regulatory definition for assuming bioequivalence in these healthy fasted Chinese male volunteers. Both formulations were generally well tolerated in the population studied. Chinese National Registry Code: 2007L02512. (Clin Ther. 2010;32:1396-1407) (C) 2010 Excerpta Medica Inc.