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      Comparison of the Pharmacokinetics of Highly Variable Drugs in Healthy Subjects Using a Partial Replicated Crossover Study: A Fixed-Dose Combination of Fimasartan 120 mg and Atorvastatin 40 mg versus Separate Tablets

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          A fixed-dose combination (FDC) of fimasartan and atorvastatin is used to treat hypertension and dyslipidemia. The peak plasma concentration (C max) of fimasartan and atorvastatin has a large intra-subject variability with a maximum coefficient of variation of 65% and 48%, respectively. Therefore, both drugs are classified as highly variable drugs. The purpose of this study was to compare the pharmacokinetics (PK) between a FDC of fimasartan 120 mg and atorvastatin 40 mg versus separate tablets in healthy male Korean subjects.

          Subjects and Methods

          A randomized, single-dose, two-treatment, three-sequence, three-period, partial replicated crossover study was conducted with a 7-day washout interval between periods. Blood samples for fimasartan and atorvastatin were collected until 48 hours after administration in each period. PK parameters were calculated using the non-compartmental method. Geometric mean ratios (GMRs) for PK parameters of FDC to loose combination and their 90% confidence intervals (90% CIs) were estimated.


          A total of 56 subjects completed the study. GMRs (90% CIs) of the C max for fimasartan and atorvastatin were 1.08 (0.93–1.24) and 1.02 (0.92–1.13), respectively. The expanded 90% CIs of both drugs using the intra-subject variability was calculated range of 0.70–1.43 and 0.73–1.38, respectively. The corresponding values of area under the concentration–time curve from zero to the last measurable time point were 1.02 (0.97–1.08) and 1.02 (0.98–1.07), respectively.


          FDC of fimasartan 120 mg and atorvastatin 40 mg between their loose combination showed similar PK characteristics.

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          Most cited references 15

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          Clinical pharmacokinetics of atorvastatin.

          Hypercholesterolaemia is a risk factor for the development of atherosclerotic disease. Atorvastatin lowers plasma low-density lipoprotein (LDL) cholesterol levels by inhibition of HMG-CoA reductase. The mean dose-response relationship has been shown to be log-linear for atorvastatin, but plasma concentrations of atorvastatin acid and its metabolites do not correlate with LDL-cholesterol reduction at a given dose. The clinical dosage range for atorvastatin is 10-80 mg/day, and it is given in the acid form. Atorvastatin acid is highly soluble and permeable, and the drug is completely absorbed after oral administration. However, atorvastatin acid is subject to extensive first-pass metabolism in the gut wall as well as in the liver, as oral bioavailability is 14%. The volume of distribution of atorvastatin acid is 381L, and plasma protein binding exceeds 98%. Atorvastatin acid is extensively metabolised in both the gut and liver by oxidation, lactonisation and glucuronidation, and the metabolites are eliminated by biliary secretion and direct secretion from blood to the intestine. In vitro, atorvastatin acid is a substrate for P-glycoprotein, organic anion-transporting polypeptide (OATP) C and H+-monocarboxylic acid cotransporter. The total plasma clearance of atorvastatin acid is 625 mL/min and the half-life is about 7 hours. The renal route is of minor importance (<1%) for the elimination of atorvastatin acid. In vivo, cytochrome P450 (CYP) 3A4 is responsible for the formation of two active metabolites from the acid and the lactone forms of atorvastatin. Atorvastatin acid and its metabolites undergo glucuronidation mediated by uridinediphosphoglucuronyltransferases 1A1 and 1A3. Atorvastatin can be given either in the morning or in the evening. Food decreases the absorption rate of atorvastatin acid after oral administration, as indicated by decreased peak concentration and increased time to peak concentration. Women appear to have a slightly lower plasma exposure to atorvastatin for a given dose. Atorvastatin is subject to metabolism by CYP3A4 and cellular membrane transport by OATP C and P-glycoprotein, and drug-drug interactions with potent inhibitors of these systems, such as itraconazole, nelfinavir, ritonavir, cyclosporin, fibrates, erythromycin and grapefruit juice, have been demonstrated. An interaction with gemfibrozil seems to be mediated by inhibition of glucuronidation. A few case studies have reported rhabdomyolysis when the pharmacokinetics of atorvastatin have been affected by interacting drugs. Atorvastatin increases the bioavailability of digoxin, most probably by inhibition of P-glycoprotein, but does not affect the pharmacokinetics of ritonavir, nelfinavir or terfenadine.
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            Cardiovascular disease risk factors: epidemiology and risk assessment.

            Current epidemiologic predictions show that the world is heading for a vascular tsunami of pandemic proportions. The number of people at high risk from cardiovascular disease is increasing; recent cohort studies suggest that only 2%-7% of the general population have no risk factors at all, and >70% of at-risk individuals have multiple risk factors. The recently published Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) study, which showed that telmisartan was as effective as ramipril in the prevention of a range of cardiovascular outcomes, enrolled a broad cross section of high-risk patients. This population was chosen to reflect the type of patients encountered in general practice, and because the proportion of high-risk individuals is increasing worldwide, the ONTARGET results will be relevant for most at-risk patients. Further analysis of the ONTARGET results may also aid in the development of risk estimation scores populated with real-life data and could also determine the impact of treatment on the long-term reduction of total cardiovascular burden (ie, absolute risk reduction). This may be a particularly useful exercise because current risk estimation charts have limitations in their scope, sensitivity, and the ability to reflect changes in risk.
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              Blood pressure and cholesterol control in hypertensive hypercholesterolemic patients: national health and nutrition examination surveys 1988-2010.

              Hypertension doubles coronary heart disease (CHD) risk. Treating hypertension only reduces CHD risk ≈25%. Treating hypercholesterolemia in hypertensive patients reduces residual CHD risk >35%.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                20 May 2020
                : 14
                : 1953-1961
                [1 ]Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital , Seoul, Republic of Korea
                Author notes
                Correspondence: SeungHwan Lee Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital , 101 Daehak-ro, Jongno-gu, Seoul03080, Republic of KoreaTel +82 2 2072 19200Fax +82 2 742 9252 Email ksyu@snu.ac.kr
                © 2020 Hwang 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).

                Page count
                Figures: 4, Tables: 4, References: 19, Pages: 9
                Original Research


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