Comparison of Pharmacokinetics of a Fixed-Dose Combination of Amlodipine/Losartan/Rosuvastatin with Concomitant Administration of Amlodipine/Losartan and Rosuvastatin in Healthy Volunteers

Abstract

Background

A fixed-dose combination (FDC) tablet formulation of amlodipine/losartan/rosuvastatin 5/100/20 mg was developed to improve medication compliance in patients with both hypertension and dyslipidemia. The comparative pharmacokinetic study was performed to compare the profile of an FDC tablet formulation of amlodipine/losartan/rosuvastatin with that of concomitant administration of a currently marketed FDC tablet of amlodipine/losartan with a rosuvastatin tablet.

Subjects and Methods

A randomized, open-label, single oral dose, two-way crossover study was conducted in 60 healthy subjects. Subjects were orally administered the FDC tablet of amlodipine/losartan/rosuvastatin and a loose combination (LC) of two tablets comprising an FDC of amlodipine/losartan and rosuvastatin. Blood samples were collected for up to 144 h post dose for pharmacokinetic evaluations. Plasma concentrations of amlodipine, losartan, EXP3174 (an active metabolite of losartan), and rosuvastatin were measured by using liquid chromatography-tandem mass spectrometry. The geometric mean ratio (GMR) and its 90% confidence interval (90% CI) in the FDC treatment to LC treatment for the area under the concentration-time curve from zero to the last quantifiable time point (AUC_last) and the maximum plasma concentration (C_max) were calculated. Safety was monitored throughout the study.

Results

The GMR (90% CI) values of AUC_last and C_max were 0.9946 (0.9663–1.0238) and 0.9690 (0.9379–1.0011) for amlodipine, 0.9855 (0.9422–1.0308) and 0.9178 (0.8349–1.0089) for losartan, 0.9814 (0.9501–1.0136) and 0.9756 (0.9313–1.0219) for EXP3174, and 0.9448 (0.8995–0.9923) and 0.9609 (0.8799–1.0494) for rosuvastatin, respectively. No clinically significant changes were observed in any of the safety parameters, including clinical laboratory tests, vital signs, electrocardiograms, and physical examinations, between the FDC treatment and the LC treatment.

Conclusion

We confirmed the pharmacokinetic equivalence of the FDC and LC treatments. This triple combination FDC formulation could be a clinically useful replacement for LC therapy.

Keywords:

• fixed-dose combination
• loose combination
• bioequivalence
• pharmacokinetics
• hypertension
• dyslipidemia

Acknowledgments

Sang-In Park was previously employed at the Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea. Her contribution to this manuscript is based on her prior employment, and the current manuscript does not reflect any position of Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine. This study was funded by Hanmi Pharm. Co., Ltd., Seoul, Republic of Korea.

Data Sharing Statement

The authors do not intend to share substantial data of this study, but they are ready to share the file of substantial data in excel format and all other study-related documents, at any specific time for any period, if the editorial board requires.

Disclosure

Jin-A Jung and Yong-Il Kim are both employees at Hanmi Pharm. Co., Ltd., Seoul, Republic of Korea. All authors declare no other conflicts of interest regarding the publication of this manuscript.