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Abstract：
BACKGROUND: Fixed-dose combinations (FDCs) of angiotensin II receptor blockers, calcium channel blockers, and statins are conventional therapeutic interventions prescribed for cardiovascular diseases. This study aimed at drawing a comparison between the pharmacokinetics and safety of an FDC and the corresponding individual formulations in healthy subjects.
METHODS: A randomized, open-label, single-dose, three-sequence, three-period, partially repeated crossover study was conducted with a cohort of healthy volunteers. A 14-day washout period was maintained between each of the three periods. In this study, candesartan cilexetil, amlodipine, and atorvastatin was administered orally as FDCs of 16/10/40 mg in study 1 and 16/5/20 mg in study 2. The maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of candesartan, amlodipine, and atorvastatin were estimated as the geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of the FDC to individual formulations. If the within-subject coefficient of variation (CVwr) of Cmax was greater than 0.3, the bioequivalence (BE) range calculated using the reference-scaled average bioequivalence was used to assess whether the 90% CI was within the BE range.
RESULTS: The GMRs (90% CIs) for the AUClast for candesartan and amlodipine were 0.9612 (0.9158-1.0089)/0.9965 (0.9550-1.0397) and 1.0033 (0.9800-1.0271)/1.0067 (0.9798-1.0344), and the GMRs (90% CIs) for Cmax were 0.9600 (0.8953-1.0294)/0.9851 (0.9368-1.0359) and 1.0198 (0.9950-1.0453)/1.0003 (0.9694-1.0321) in studies 1 and 2, respectively. The extended BE ranges calculated from the CVwr of the Cmax of atorvastatin were 0.7814-1.2797 and 0.7415-1.3485, respectively. The GMRs (90% CIs) for the AUClast of atorvastatin were 1.0532 (1.0082-1.1003)/1.0252 (0.9841-1.0680), and the GMRs (90% CIs) for Cmax were 1.0630 (0.9418-1.1997)/0.9888 (0.8792-1.1120) in studies 1 and 2, respectively.
CONCLUSIONS: The Cmax and AUClast values of candesartan cilexetil/amlodipine/atorvastatin 16/10/40 mg and 16/5/20 mg, respectively, were within the BE ranges. There were no clinically significant differences in safety between the two formulations.
BACKGROUND: ClinicalTrials.gov identifier, study 1: NCT04478097; study 2: NCT04627207.
METHODS: A randomized, open-label, single-dose, three-sequence, three-period, partially repeated crossover study was conducted with a cohort of healthy volunteers. A 14-day washout period was maintained between each of the three periods. In this study, candesartan cilexetil, amlodipine, and atorvastatin was administered orally as FDCs of 16/10/40 mg in study 1 and 16/5/20 mg in study 2. The maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of candesartan, amlodipine, and atorvastatin were estimated as the geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of the FDC to individual formulations. If the within-subject coefficient of variation (CVwr) of Cmax was greater than 0.3, the bioequivalence (BE) range calculated using the reference-scaled average bioequivalence was used to assess whether the 90% CI was within the BE range.
RESULTS: The GMRs (90% CIs) for the AUClast for candesartan and amlodipine were 0.9612 (0.9158-1.0089)/0.9965 (0.9550-1.0397) and 1.0033 (0.9800-1.0271)/1.0067 (0.9798-1.0344), and the GMRs (90% CIs) for Cmax were 0.9600 (0.8953-1.0294)/0.9851 (0.9368-1.0359) and 1.0198 (0.9950-1.0453)/1.0003 (0.9694-1.0321) in studies 1 and 2, respectively. The extended BE ranges calculated from the CVwr of the Cmax of atorvastatin were 0.7814-1.2797 and 0.7415-1.3485, respectively. The GMRs (90% CIs) for the AUClast of atorvastatin were 1.0532 (1.0082-1.1003)/1.0252 (0.9841-1.0680), and the GMRs (90% CIs) for Cmax were 1.0630 (0.9418-1.1997)/0.9888 (0.8792-1.1120) in studies 1 and 2, respectively.
CONCLUSIONS: The Cmax and AUClast values of candesartan cilexetil/amlodipine/atorvastatin 16/10/40 mg and 16/5/20 mg, respectively, were within the BE ranges. There were no clinically significant differences in safety between the two formulations.
BACKGROUND: ClinicalTrials.gov identifier, study 1: NCT04478097; study 2: NCT04627207.
摘要：
背景：血管紧张素II受体阻滞剂的固定剂量组合（FDC），钙通道阻滞剂，和他汀类药物是心血管疾病的常规治疗干预措施。这项研究旨在比较健康受试者中FDC和相应的单个制剂的药代动力学和安全性。
方法：随机，开放标签，单剂量,三个序列，三个时期，我们对一组健康志愿者进行了部分重复的交叉研究.在三个时期中的每一个之间维持14天的清除期。在这项研究中,坎地沙坦酯,氨氯地平,阿托伐他汀在研究1中以16/10/40mg的FDC口服给药，在研究2中以16/5/20mg的FDC口服给药。从时间零到坎地沙坦的最后可量化浓度（AUClast）的时间，最大血浆浓度（Cmax）和血浆浓度-时间曲线下面积，氨氯地平,和阿托伐他汀被估计为FDC与单个制剂的几何平均比率(GMR)和90%置信区间(CIs)。如果Cmax的受试者内变异系数(CVwr)大于0.3,则使用参考缩放平均生物等效性计算的生物等效性(BE)范围来评估90%CI是否在BE范围内。
结果：坎地沙坦和氨氯地平的AUClast的GMR（90％CI）为0.9612（0.9158-1.0089）/0.9965（0.9550-1.0397）和1.0033（0.9800-1.0271）/1.0067（0.9798-1.0344），在研究1和2中，Cmax的GMR（90％CI）分别为0.9600（0.8953-1.0294）/0.9851（0.9368-1.0359）和1.0198（0.9950-1.0453）/1.0003（0.9694-1.0321）。根据阿托伐他汀Cmax的CVwr计算的延长BE范围分别为0.7814-1.2797和0.7415-1.3485。阿托伐他汀的AUClast的GMR（90％CI）为1.0532（1.0082-1.1003）/1.0252（0.9841-1.0680），在研究1和2中，Cmax的GMR（90％CI）分别为1.0630（0.9418-1.1997）/0.9888（0.8792-1.1120）。
结论：坎地沙坦酯/氨氯地平/阿托伐他汀16/10/40mg和16/5/20mg的Cmax和AUClast值，分别,在BE范围内。两种制剂之间的安全性没有临床上的显著差异。
背景：ClinicalTrials.gov标识符，研究1：NCT04478097；研究2：NCT04627207。
方法：随机，开放标签，单剂量,三个序列，三个时期，我们对一组健康志愿者进行了部分重复的交叉研究.在三个时期中的每一个之间维持14天的清除期。在这项研究中,坎地沙坦酯,氨氯地平,阿托伐他汀在研究1中以16/10/40mg的FDC口服给药，在研究2中以16/5/20mg的FDC口服给药。从时间零到坎地沙坦的最后可量化浓度（AUClast）的时间，最大血浆浓度（Cmax）和血浆浓度-时间曲线下面积，氨氯地平,和阿托伐他汀被估计为FDC与单个制剂的几何平均比率(GMR)和90%置信区间(CIs)。如果Cmax的受试者内变异系数(CVwr)大于0.3,则使用参考缩放平均生物等效性计算的生物等效性(BE)范围来评估90%CI是否在BE范围内。
结果：坎地沙坦和氨氯地平的AUClast的GMR（90％CI）为0.9612（0.9158-1.0089）/0.9965（0.9550-1.0397）和1.0033（0.9800-1.0271）/1.0067（0.9798-1.0344），在研究1和2中，Cmax的GMR（90％CI）分别为0.9600（0.8953-1.0294）/0.9851（0.9368-1.0359）和1.0198（0.9950-1.0453）/1.0003（0.9694-1.0321）。根据阿托伐他汀Cmax的CVwr计算的延长BE范围分别为0.7814-1.2797和0.7415-1.3485。阿托伐他汀的AUClast的GMR（90％CI）为1.0532（1.0082-1.1003）/1.0252（0.9841-1.0680），在研究1和2中，Cmax的GMR（90％CI）分别为1.0630（0.9418-1.1997）/0.9888（0.8792-1.1120）。
结论：坎地沙坦酯/氨氯地平/阿托伐他汀16/10/40mg和16/5/20mg的Cmax和AUClast值，分别,在BE范围内。两种制剂之间的安全性没有临床上的显著差异。
背景：ClinicalTrials.gov标识符，研究1：NCT04478097；研究2：NCT04627207。
