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Comparison of the Pharmacokinetics of Highly Variable Drugs in Healthy Subjects Using a Partial Replicated Crossover Study: A Fixed-Dose Combination of Fimasartan 120 mg and Atorvastatin 40 mg versus Separate Tablets.
Drug Design, Development and Therapy ( IF 4.8 ) Pub Date : 2020-05-20 , DOI: 10.2147/dddt.s233732 Jun Gi Hwang 1 , Kyung-Sang Yu 1 , SeungHwan Lee 1
Drug Design, Development and Therapy ( IF 4.8 ) Pub Date : 2020-05-20 , DOI: 10.2147/dddt.s233732 Jun Gi Hwang 1 , Kyung-Sang Yu 1 , SeungHwan Lee 1
Affiliation
Purpose: A fixed-dose combination (FDC) of fimasartan and atorvastatin is used to treat hypertension and dyslipidemia. The peak plasma concentration (Cmax) of fimasartan and atorvastatin has a large intra-subject variability with a maximum coefficient of variation of 65% and 48%, respectively. Therefore, both drugs are classified as highly variable drugs. The purpose of this study was to compare the pharmacokinetics (PK) between a FDC of fimasartan 120 mg and atorvastatin 40 mg versus separate tablets in healthy male Korean subjects.
Subjects and Methods: A randomized, single-dose, two-treatment, three-sequence, three-period, partial replicated crossover study was conducted with a 7-day washout interval between periods. Blood samples for fimasartan and atorvastatin were collected until 48 hours after administration in each period. PK parameters were calculated using the non-compartmental method. Geometric mean ratios (GMRs) for PK parameters of FDC to loose combination and their 90% confidence intervals (90% CIs) were estimated.
Results: A total of 56 subjects completed the study. GMRs (90% CIs) of the Cmax for fimasartan and atorvastatin were 1.08 (0.93– 1.24) and 1.02 (0.92– 1.13), respectively. The expanded 90% CIs of both drugs using the intra-subject variability was calculated range of 0.70– 1.43 and 0.73– 1.38, respectively. The corresponding values of area under the concentration–time curve from zero to the last measurable time point were 1.02 (0.97– 1.08) and 1.02 (0.98– 1.07), respectively.
Conclusion: FDC of fimasartan 120 mg and atorvastatin 40 mg between their loose combination showed similar PK characteristics.
Keywords: fixed-dose combination, partial replicated design, fimasartan, atorvastatin, pharmacokinetics
中文翻译：
使用部分复制交叉研究比较高度可变药物在健康受试者中的药代动力学：非马沙坦 120 毫克和阿托伐他汀 40 毫克与单独片剂的固定剂量组合。
目的：非马沙坦和阿托伐他汀的固定剂量组合（FDC）用于治疗高血压和血脂异常。非马沙坦和阿托伐他汀的峰血浆浓度 ( Cmax ) 具有较大的受试者内变异性，最大变异系数分别为 65% 和 48%。因此，这两种药物都被归类为高度可变的药物。本研究的目的是在健康的韩国男性受试者中比较非马沙坦 120 毫克和阿托伐他汀 40 毫克的 FDC 与单独的片剂之间的药代动力学 (PK)。
主题和方法：进行了一项随机、单剂量、两次治疗、三序列、三期、部分重复的交叉研究，期间之间有 7 天的清除间隔。收集非马沙坦和阿托伐他汀的血样，直到每个时期给药后 48 小时。PK 参数使用非隔室法计算。估计了 FDC 与松散组合的 PK 参数的几何平均比 (GMR) 及其 90% 置信区间 (90% CI)。
结果：共有 56 名受试者完成了研究。C max的 GMR (90% CI)非马沙坦和阿托伐他汀分别为 1.08 (0.93–1.24) 和 1.02 (0.92–1.13)。使用受试者内变异性计算出两种药物的扩展 90% CI 范围分别为 0.70-1.43 和 0.73-1.38。从零到最后一个可测量时间点的浓度-时间曲线下面积的相应值分别为1.02（0.97-1.08）和1.02（0.98-1.07）。
结论：非马沙坦 120 mg 和阿托伐他汀 40 mg 松散组合的 FDC 表现出相似的 PK 特征。
关键词：固定剂量组合，部分重复设计，非马沙坦，阿托伐他汀，药代动力学
更新日期：2020-05-20
Subjects and Methods: A randomized, single-dose, two-treatment, three-sequence, three-period, partial replicated crossover study was conducted with a 7-day washout interval between periods. Blood samples for fimasartan and atorvastatin were collected until 48 hours after administration in each period. PK parameters were calculated using the non-compartmental method. Geometric mean ratios (GMRs) for PK parameters of FDC to loose combination and their 90% confidence intervals (90% CIs) were estimated.
Results: A total of 56 subjects completed the study. GMRs (90% CIs) of the Cmax for fimasartan and atorvastatin were 1.08 (0.93– 1.24) and 1.02 (0.92– 1.13), respectively. The expanded 90% CIs of both drugs using the intra-subject variability was calculated range of 0.70– 1.43 and 0.73– 1.38, respectively. The corresponding values of area under the concentration–time curve from zero to the last measurable time point were 1.02 (0.97– 1.08) and 1.02 (0.98– 1.07), respectively.
Conclusion: FDC of fimasartan 120 mg and atorvastatin 40 mg between their loose combination showed similar PK characteristics.
Keywords: fixed-dose combination, partial replicated design, fimasartan, atorvastatin, pharmacokinetics
中文翻译：
使用部分复制交叉研究比较高度可变药物在健康受试者中的药代动力学：非马沙坦 120 毫克和阿托伐他汀 40 毫克与单独片剂的固定剂量组合。
目的：非马沙坦和阿托伐他汀的固定剂量组合（FDC）用于治疗高血压和血脂异常。非马沙坦和阿托伐他汀的峰血浆浓度 ( Cmax ) 具有较大的受试者内变异性，最大变异系数分别为 65% 和 48%。因此，这两种药物都被归类为高度可变的药物。本研究的目的是在健康的韩国男性受试者中比较非马沙坦 120 毫克和阿托伐他汀 40 毫克的 FDC 与单独的片剂之间的药代动力学 (PK)。
主题和方法：进行了一项随机、单剂量、两次治疗、三序列、三期、部分重复的交叉研究，期间之间有 7 天的清除间隔。收集非马沙坦和阿托伐他汀的血样，直到每个时期给药后 48 小时。PK 参数使用非隔室法计算。估计了 FDC 与松散组合的 PK 参数的几何平均比 (GMR) 及其 90% 置信区间 (90% CI)。
结果：共有 56 名受试者完成了研究。C max的 GMR (90% CI)非马沙坦和阿托伐他汀分别为 1.08 (0.93–1.24) 和 1.02 (0.92–1.13)。使用受试者内变异性计算出两种药物的扩展 90% CI 范围分别为 0.70-1.43 和 0.73-1.38。从零到最后一个可测量时间点的浓度-时间曲线下面积的相应值分别为1.02（0.97-1.08）和1.02（0.98-1.07）。
结论：非马沙坦 120 mg 和阿托伐他汀 40 mg 松散组合的 FDC 表现出相似的 PK 特征。
关键词：固定剂量组合，部分重复设计，非马沙坦，阿托伐他汀，药代动力学
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