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      Pharmacokinetics, pharmacodynamics and safety of CKD-519, a CETP inhibitor, in healthy subjects

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          Abstract

          CKD-519 is a selective and potent cholesteryl ester transfer protein (CETP) inhibitor being developed for the treatment of dyslipidemia to raise high-density lipoprotein cholesterol. We investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of CKD-519 in healthy adult subjects. A randomized, double-blinded, placebo-controlled, single ascending dose study was performed. Eight healthy subjects were enrolled in each CKD-519 dose group (25, 50, 100, 200, or 400 mg) and randomized to CKD-519 (n=6) or matching placebo (n=2). CKD-519 reached the maximum plasma concentration (C max) at 5–6 h post-dose, and had a long terminal half-life ranging between 40–70 h. The area under the plasma concentration–time curve (AUC) and C max increased with the dose, however, C max and AUC normalized by dose decreased with each incremental dose. CETP activity decreased with dose, and the maximum decrease (63%–83%) was observed at 6–8 h post-dose. A sigmoid E max model best described the relationship between CKD-519 plasma concentrations and CETP activity with an EC 50 of 17.3 ng/mL. Overall, 11 adverse events (AEs) were observed. All AEs were mild or moderate in intensity, and resolved without any complications. There were no clinically significant effects on blood pressure. In conclusion, single doses of CKD-519 up to 400 mg were well tolerated and showed potent inhibition of CETP activity.

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          Most cited references 16

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          Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study.

           G Heiss,  ,  Jane Ballantyne (2001)
          Despite consensus on the need for blood cholesterol reductions to prevent coronary heart disease (CHD), available evidence on optimal cholesterol levels or the added predictive value of additional lipids is sparse. After 10 years follow-up of 12 339 middle-aged participants free of CHD in the Atherosclerosis Risk in Communities Study (ARIC), 725 CHD events occurred. The lowest incidence was observed in those at the lowest LDL cholesterol (LDL-C) quintile, with medians of 88 mg/dL in women and 95 mg/dL in men, and risk accelerated at higher levels, with relative risks (RRs) for the highest quintile of 2.7 in women and 2.5 in men. LDL-C, HDL-C, lipoprotein(a) [Lp(a)], and in women but not men, triglycerides (TG) were all independent CHD predictors, providing an RR, together with blood pressure, smoking, and diabetes, of 13.5 in women and 4.9 in men. Lp(a) was less significant in blacks than whites. Prediction was not enhanced by HDL-C density subfractions or apolipoproteins (apo) A-I or B. Despite strong univariate associations, apoB did not contribute to risk prediction in subgroups with elevated TG, with lower LDL-C, or with high apoB relative to LDL-C. Optimal LDL-C values are <100 mg/dL in both women and men. LDL-C, HDL-C, TG, and Lp(a), without additional apolipoproteins or lipid subfractions, provide substantial CHD prediction, with much higher RR in women than men.
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            Plasma cholesteryl ester transfer protein.

             A R Tall (1993)
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              Cardiovascular disease epidemiology in Asia: an overview.

              Cardiovascular disease (CVD) is the leading cause of death in the world and half of the cases of CVD are estimated to occur in Asia. Compared with Western countries, most Asian countries, except for Japan, South Korea, Singapore and Thailand, have higher age-adjusted mortality from CVD. In Japan, the mortality from CVD, especially stroke, has declined continuously from the 1960s to the 2000s, which has contributed to making Japan into the top-ranking country for longevity in the world. Hypertension and smoking are the most notable risk factors for stroke and coronary artery disease, whereas dyslipidemia and diabetes mellitus are risk factors for ischemic heart disease and ischemic stroke. The nationwide approach to hypertension prevention and control has contributed to a substantial decline in stroke mortality in Japan. Recent antismoking campaigns have contributed to a decline in the smoking rate among men. Conversely, the prevalence of dyslipidemia and diabetes mellitus increased from the 1980s to the 2000s and, therefore, the population-attributable risks of CVD for dyslipidemia and diabetes mellitus have increased moderately. To prevent future CVD in Asia, the intensive prevention programs for hypertension and smoking should be continued and that for emerging metabolic risk factors should be intensified in Japan. The successful intervention programs in Japan can be applied to other Asian countries.
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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
                2016
                15 November 2016
                : 10
                : 3763-3770
                Affiliations
                [1 ]Department of Clinical Pharmacology, Severance Hospital, Yonsei University College of Medicine, Seoul
                [2 ]Department of Pharmaceutical Medicines and Regulatory Science, Colleges of Medicine and Pharmacy, Yonsei University, Incheon
                [3 ]Chong Kun Dang Clinical Research, Chong Kun Dang Pharmaceutical Corp.
                [4 ]Chong Kun Dang Research Institute, Chong Kun Dang Pharmaceutical Corp.
                [5 ]Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea
                Author notes
                Correspondence: Min Soo Park, Department of Clinical Pharmacology, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea, Tel +82 2 2228 0400, Fax +82 2 2227 7890, Email minspark@ 123456yuhs.ac
                Article
                dddt-10-3763
                10.2147/DDDT.S120387
                5117885
                © 2016 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.

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                Original Research

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