阿托伐他汀/ω-3 酸乙酯固定剂量复方制剂与相应松散复方在健康韩国男性受试者中的药代动力学比较。

Pharmacokinetic Comparison Between a Fixed-Dose Combination of Atorvastatin/Omega-3-Acid Ethyl Esters and the Corresponding Loose Combination in Healthy Korean Male Subjects.

机构信息

Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.

Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Republic of Korea.

出版信息

Drug Des Devel Ther. 2024 Feb 8;18:395-406. doi: 10.2147/DDDT.S435885. eCollection 2024.

PURPOSE

Statins are widely used in combination with omega-3 fatty acids for the treatment of patients with dyslipidemia. The aim of this study was to compare the pharmacokinetic (PK) profiles of atorvastatin and omega-3-acid ethyl esters between fixed-dose combination (FDC) and loose combination in healthy subjects.

METHODS

A randomized, open-label, single-dose, 2-sequence, 2-treatment, 4-period replicated crossover study was performed. Subjects were randomly assigned to one of the 2 sequences and alternately received four FDC soft capsules of atorvastatin/omega-3-acid ethyl esters (10/1000 mg) or a loose combination of atorvastatin tablets (10 mg × 4) and omega-3-acid ethyl ester soft capsules (1000 mg× 4) for four periods, each period accompanied by a high-fat meal. Serial blood samples were collected for PK analysis of atorvastatin, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). PK parameters were calculated by a non-compartmental analysis. The geometric mean ratio (GMR) and its 90% confidence interval (CI) of the FDC to the loose combination were calculated to compare PK parameters.

RESULTS

A total of 43 subjects completed the study as planned. The GMR (90% CI) of FDC to loose combination for maximum concentration (C) and area under the time-concentration curve from zero to the last measurable point (AUC) were 1.0931 (1.0054-1.1883) and 0.9885 (0.9588-1.0192) for atorvastatin, 0.9607 (0.9068-1.0178) and 0.9770 (0.9239-1.0331) for EPA, and 0.9961 (0.9127-1.0871) and 0.9634 (0.8830-1.0512) for DHA, respectively. The intra-subject variability for C and AUC of DHA was 30.8% and 37.5%, respectively, showing high variability. Both the FDC and the loose combination were safe and well tolerated.

CONCLUSION

The FDC of atorvastatin and omega-3-acid ethyl esters showed comparable PK characteristics to the corresponding loose combination, offering a convenient therapeutic option for the treatment of dyslipidemia.

目的

他汀类药物与 ω-3 脂肪酸联合用于治疗血脂异常患者。本研究旨在比较固定剂量复方制剂（FDC）和松散联合制剂在健康受试者中的药代动力学（PK）特征。

方法

这是一项随机、开放标签、单剂量、2 序列、2 治疗、4 周期重复交叉研究。受试者随机分配到 2 个序列中的 1 个，并在 4 个周期中交替接受阿托伐他汀/ω-3 酸乙酯 FDC 软胶囊（10/1000mg）或阿托伐他汀片剂（10mg×4）和 ω-3 酸乙酯软胶囊（1000mg×4）的松散组合，每个周期均伴随高脂肪餐。采集系列血样进行阿托伐他汀、二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）的 PK 分析。通过非房室分析计算 PK 参数。计算 FDC 与松散组合的几何均数比值（GMR）及其 90%置信区间（CI），以比较 PK 参数。

结果

共有 43 名受试者按计划完成了研究。阿托伐他汀 C 和 AUC 的 FDC 与松散组合的 GMR（90%CI）分别为 1.0931（1.0054-1.1883）和 0.9885（0.9588-1.0192），EPA 分别为 0.9607（0.9068-1.0178）和 0.9770（0.9239-1.0331），DHA 分别为 0.9961（0.9127-1.0871）和 0.9634（0.8830-1.0512）。DHA 的 C 和 AUC 的个体内变异性分别为 30.8%和 37.5%，显示出高度的变异性。FDC 和松散组合均安全且耐受良好。