Pharmacokinetic comparison of a fixed-dose combination versus concomitant administration of amlodipine, olmesartan, and rosuvastatin in healthy adult subjects

Drug Design, Development and Therapy Dovepress open access to scientific and medical research Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 88.198.20.149 on 18-Aug-2019 For personal use only. Open Access Full Text Article ORIGINAL RESEARCH Pharmacokinetic comparison of a fixed-dose combination versus concomitant administration of amlodipine, olmesartan, and rosuvastatin in healthy adult subjects This article was published in the following Dove Press journal: Drug Design, Development and Therapy Minkyung Oh 1 Jae-Gook Shin 1,2 Sangzin Ahn 1 Bo Hoon Kim 3 Ji Yeon Kim 3 Hyun Ju Shin 4 Hyun Ju Shin 4 Jong-Lyul Ghim 1,2 1 Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea; 2Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Republic of Korea; 3Formulation Research Team, Daewoong Pharma, Seoul, Republic of Korea; 4Clinical Research Team, Daewoong Pharma, Seoul, Republic of Korea Objective: The aim of this study was to compare the pharmacokinetic (PK) and safety profiles of a fixed dose combination (FDC) formulation and co-administration of amlodipine, olmesartan, and rosuvastatin. Materials and methods: This study was an open-label, randomized, cross-over design conducted in healthy male volunteers. All subjects received either a single FDC tablet containing amlodipine 10 mg/olmesartan 40 mg/rosuvastatin 20 mg, or were co-administered an FDC tablet containing amlodipine 10 mg/olmesartan 40 mg and a tablet containing rosuvastatin 20 mg, for each period, with 14-day washout periods. Plasma concentrations of amlodipine, olmesartan, and rosuvastatin were measured by liquid chromatography tandem mass spectrometry. Safety was evaluated by measuring vital signs, clinical laboratory parameters, physical examinations, and medical interviews. Results: Sixty-four subjects were enrolled, and 54 completed the study. The geometric mean ratios and 90% CI for the maximum plasma concentration (Cmax) and area under the curve from time zero to the last sampling time (AUCt) were 1.0716 (1.0369,1.1074) and 1.0497 (1.0243,1.0757) for amlodipine, 1.0396 (0.9818,1.1009) and 1.0138 (0.9716,1.0578) for olmesartan, and 1.0257 (0.9433,1.1152) and 1.0043 (0.9453,1.0669) for rosuvastatin. Fourteen cases of adverse events occurred in 12 subjects. There was no statistically significant clinical difference between the formulation groups. Conclusion: The 90% CI of the primary PK parameters were within the acceptance bioequivalence criteria, which is ln (0.8) and ln (1.25). These results indicate that the FDC formulation and co-administration of amlodipine, olmesartan and rosuvastatin are pharmacokinetically bioequivalent and have similar safety profiles. Keywords: fixed-dose combination, pharmacokinetics, amlodipine, olmesartan, rosuvastatin Introduction Correspondence: Jong-Lyul Ghim Department of Pharmacology and Clinical Pharmacology, Inje University College of Medicine and Busan Paik Hospital, 75 Bokji-ro, Busanjin-Gu, Busan 47392, Republic of Korea Tel +82 105 639 3635 Fax +82 51 893 1232 Email 991 submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2019:13 991–997 DovePress © 2019 Oh et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). http://doi.org/10.2147/DDDT.S202730 Powered by TCPDF (www.tcpdf.org) Cardiovascular disease (CVD) accounts for about 34.3% of all deaths, and the total cost of CVD is 503.2 billion USD, causing serious social and economic impact on individuals and governments.1 According to the annual report on causes of death, released by the National Statistical Office of Korea, the Korean CVD mortality rate decreased by 0.4 (−0.4%) to 113.1 per 100,000, in 2013. In Korea, CVD was ranked second leading cause of death in 2013, after cancer (149.0 per 100,000).2 Dovepress Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 88.198.20.149 on 18-Aug-2019 For personal use only. Oh et al Amlodipine and olmesartan are antihypertensive agents with different mechanisms. Amlodipine is a dihydropyridine calcium channel blocker that blocks Ca2+ from entering the cell membrane of the heart and vascular smooth muscle, which directly relaxes the smooth muscle to lower blood pressure. Olmesartan, is an angiotensin II receptor blocker that blocks the binding of angiotensin II to the receptor that contracts the blood vessels. Together, they are often used as a combination therapy for the treatment of hypertensive patients who are unresponsive to single therapy.3,4 Hyperlipidemia is a CVD that is characterized by an increase in serum concentrations of cholesterol, triglycerides, or both, resulting from a metabolic lipoprotein abnormality. It is a major risk factor for arteriosclerosis and increases the risk of coronary artery disease. Rosuvastatin is widely used to treat hyperlipidemia. It lowers the concentration of total cholesterol and LDL-cholesterol in serum by inhibiting 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase which inhibits the synthesis of mevalonate. Compared to other hyperlipidemic agents, rosuvastatin, in particular, has a high affinity for HMG-CoA reductase and a high inhibitory effect, which effectively reduces LDL cholesterol and increases HDL cholesterol.5 Hypertension is often associated with increased blood lipids that cause arteriosclerosis. Hypertension and hyperlipidemia are synergistic at the onset and exacerbation of CVD, so treatment should address both morbidities.6 In addition, hypertension and dyslipidemia are more likely to occur in patients with chronic illnesses. As the combined use of therapeutic agents increases, so too does the number of separate medications the patient is required to take, which can reduce medication compliance, leading to poor treatment outcomes. Therefore, reducing the number of separate medications taken by the patient can importantly contribute to good therapeutic results.7,8 The aim of this study was to compare the PK profile and safety of an FDC formulation and co-administration of amlodipine, olmesartan and rosuvastatin in healthy male subjects. Materials and methods The study protocol was approved by the Institutional Review Board of Inje University Busan Paik Hospital and the Korean Ministry of Food and Drug Safety (KMFDS) (ClinicalTrials.gov: NCT (...truncated)