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      Pharmacokinetic interactions and tolerability of rosuvastatin and ezetimibe: an open-label, randomized, multiple-dose, crossover study in healthy male volunteers

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          Abstract

          Purpose

          Rosuvastatin is a synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor that effectively reduces low-density lipoprotein cholesterol levels. However, statin monotherapy does not always achieve acceptable low-density lipoprotein cholesterol levels in patients with severe hypercholesterolemia. Ezetimibe, a selective cholesterol-absorption inhibitor, is approved for use as a monotherapy or combination therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors for patients with hypercholesterolemia. The aim of this study was to examine the pharmacokinetics (PKs) of drug interactions between rosuvastatin and ezetimibe, and the tolerability of combined administration in healthy Korean male volunteers.

          Subjects and methods

          Healthy subjects (n=24) were randomly allocated to 3 treatment groups: rosuvastatin (20 mg) alone, ezetimibe (10 mg) alone, and rosuvastatin (20 mg) plus ezetimibe (10 mg). The drugs were taken once every 24 hours over a period of 10 days. Blood samples were collected to analyze steady-state PKs.

          Results

          All adverse events observed during the study were mild, and the frequency was no higher for combined administration than for mono administration. For rosuvastatin, the steady-state mean ratios (90% CI) of the combined over the single dose were 1.076 (1.019–1.136) for AUC τ,ss and 1.099 (1.003–1.204) for concentration at steady-state, respectively. In the case of free and total ezetimibe, the steady-state ratios of AUC τ,ss and concentration at steady-state were 1.131 (1.051–1.218) and 1.182 (1.038–1.346), and 1.055 (0.969–1.148) and 0.996 (0.873–1.135), respectively.

          Conclusion

          Combined administration of rosuvastatin and ezetimibe was well tolerated. No clinically significant PK interactions between rosuvastatin and ezetimibe were observed when the 2 drugs were administered concomitantly.

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          Most cited references 20

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          Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial.

          Despite the established efficacy of statins, many patients do not achieve recommended LDL cholesterol (LDL-C) goals. Contributing factors may be inadequate dosing, increased risk for adverse effects with high-dose monotherapy, and increased potential for intolerance and adverse effects with combinations of available agents. In a double-blind study, 628 patients with baseline LDL-C 145 to 250 mg/dL and triglycerides < or =350 mg/dL were randomly assigned to receive 1 of the following for 12 weeks: ezetimibe (10 mg/d); atorvastatin (10, 20, 40, or 80 mg/d); ezetimibe (10 mg) plus atorvastatin (10, 20, 40, or 80 mg/d); or placebo. The primary efficacy end point was percentage reduction in LDL-C for pooled ezetimibe plus atorvastatin versus pooled atorvastatin treatment groups. Ezetimibe plus atorvastatin significantly improved LDL-C, HDL cholesterol (HDL-C), triglycerides, total cholesterol:HDL-C, and high-sensitivity C-reactive protein (hs-CRP) compared with atorvastatin alone (P<0.01). Coadministration of ezetimibe provided a significant additional 12% LDL-C reduction, 3% HDL-C increase, 8% triglyceride reduction, and 10% hs-CRP reduction versus atorvastatin alone. Ezetimibe plus atorvastatin provided LDL-C reductions of 50% to 60%, triglyceride reductions of 30% to 40%, and HDL-C increases of 5% to 9%, depending on atorvastatin dose. LDL-C reductions with ezetimibe plus 10 mg atorvastatin (50%) and 80 mg atorvastatin alone (51%) were similar. Ezetimibe plus atorvastatin was well tolerated, with a safety profile similar to atorvastatin alone and to placebo. When coadministered with atorvastatin, ezetimibe provided significant incremental reductions in LDL-C and triglycerides and increases in HDL-C. Coadministration of ezetimibe and atorvastatin offers a well-tolerated and highly efficacious new treatment option for patients with hypercholesterolemia.
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            Changes in risk factors and the decline in mortality from cardiovascular disease. The Framingham Heart Study.

            A decline in mortality from cardiovascular disease over the past 30 years has been well documented, but the reasons for the decline remain unclear. We analyzed the 10-year incidence of cardiovascular disease and death from cardiovascular disease in three groups of men who were 50 to 59 years old at base line in 1950, 1960, and 1970 (the 1950, 1960, and 1970 cohorts) in order to determine the contribution of secular trends in the incidence of cardiovascular disease, risk factors, and medical care to the decline in mortality. The 10-year cumulative mortality from cardiovascular disease in the 1970 cohort was 43 percent less than that in the 1950 cohort and 37 percent less than that in the 1960 cohort (P = 0.04 by log-rank test). Among the men who were free of cardiovascular disease at base line, the 10-year cumulative incidence of cardiovascular disease declined approximately 19 percent, from 190 per 1000 in the 1950 cohort to 154 per 1000 in the 1970 cohort (0.10 less than P less than 0.20 by chi-square test), whereas the 10-year rate of death from cardiovascular disease declined 60 percent (relative risk for the 1950 cohort as compared with the 1970 cohort, 2.53; 95 percent confidence interval, 1.22 to 5.97). Significant improvements were found in risk factors for cardiovascular disease among the men initially free of cardiovascular disease in the 1970 cohort as compared with those in the 1950 cohort, including a lower serum cholesterol level (mean +/- SD, 5.72 +/- 0.98 mmol per liter [221 +/- 38 mg per deciliter], as compared with 5.90 +/- 1.03 mmol per liter [228 +/- 40 mg per deciliter]) and a lower systolic blood pressure (mean +/- SD, 135 +/- 19 mm Hg, as compared with 139 +/- 25 mm Hg), better management of hypertension (22 percent vs. 0 percent were receiving antihypertensive medication), and reduced cigarette smoking (34 percent vs. 56 percent). We propose that these improvements may have had more pronounced effects on mortality from cardiovascular disease than on the incidence of cardiovascular disease in this population. Our data suggest that the improvement in cardiovascular risk factors in the 1970 cohort may have been an important contributor to the 60 percent decline in mortality in that group as compared with the 1950 cohort, although a decline in the incidence of cardiovascular disease and improved medical interventions may also have contributed to the decline in mortality.
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              Rosuvastatin: Beyond the cholesterol-lowering effect

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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2018
                11 April 2018
                : 12
                : 815-821
                Affiliations
                [1 ]Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea
                [2 ]Clinical Research Team, Hanmi Pharmaceutical Co. Ltd., Seoul, Republic of Korea
                Author notes
                Correspondence: Hyeong-Seok Lim, Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea, Tel +82 2 3010 4613, Fax +82 2 3010 4623, Email mdlhs@ 123456amc.seoul.kr
                Article
                dddt-12-815
                10.2147/DDDT.S158408
                5903480
                © 2018 Kim 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.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                tolerability, rosuvastatin, ddi, pharmacokinetics, ezetimibe

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