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Randomized Controlled Trial
. 2024 Feb 8:18:395-406.
doi: 10.2147/DDDT.S435885. eCollection 2024.

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

Juyoung Khwarg  1 , Soyoung Lee  1   2 , In-Jin Jang  1 , Won-Ho Kang  3 , Hye Jung Lee  4 , Kyu Yeon Kim  4 , Ki-Sun Jeong  4 , Chongho Won  4 , Youn Woong Choi  5 , Dae Chul Ha  5 , RaeHoon Jung  5 , Min-Gu Han  5 , Won Tae Jung  6 , Kyu-Yeol Nam  6 , YeSeul Kim  6 , Kyung-Sang Yu  1 , Jaeseong Oh  1   7
Affiliations
Randomized Controlled Trial

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

Juyoung Khwarg et al. Drug Des Devel Ther. .

Abstract

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 (Cmax) and area under the time-concentration curve from zero to the last measurable point (AUClast) 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 Cmax and AUClast 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.

Keywords: cardiovascular disease; pharmacokinetics.

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Conflict of interest statement

Won-Ho Kang, Youn Woong Choi, Dae Chul Ha, RaeHoon Jung, Min-Gu Han, Won Tae Jung, Kyu-Yeol Nam, and YeSeul Kim are employees of Korea United Pharm. Inc. Hye Jung Lee, Kyu Yeon Kim, Ki-Sun Jeong, and Chongho Won are employees of Caleb Multilab, Inc. The other authors do not have any conflicts of interest for this study.

Figures

None
Graphical abstract
Figure 1
Figure 1
Summary of the study design.
Figure 2
Figure 2
Mean plasma concentration-time profiles of (A) atorvastatin, baseline adjusted (B) EPA, and (C) DHA in linear scale following administration of FDC of atorvastatin/omega-3-acid ethyl esters (10/1000 mg × 4) or loose combination of atorvastatin tablet (10 mg × 4) and omega-3-acid ethyl esters soft capsule (1000 mg× 4).
Figure 3
Figure 3
Mean plasma concentration-time profiles of (A) EPA and (B) DHA on a linear scale following administration of FDCs of atorvastatin/omega-3-acid ethyl esters (10/1000 mg × 4) or a loose combination of atorvastatin tablet (10 mg × 4) and omega-3-acid ethyl ester soft capsule (1000 mg × 4).
Figure 4
Figure 4
Individual (A) Cmax and (B) AUClast of atorvastatin, baseline adjusted (C) Cmax and (D) AUClast of EPA, baseline adjusted (E) Cmax and (F) AUClast of DHA following administration of FDC of atorvastatin/omega-3-acid ethyl esters (10/1000 mg × 4) or loose combination of atorvastatin tablet (10 mg × 4) and omega-3-acid ethyl esters soft capsule (1000 mg× 4).
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