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

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          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.

          Most cited references15

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          Fixed-dose combinations improve medication compliance: a meta-analysis.

          Compliance with treatment is a sine qua non for successful treatment of chronic conditions like hypertension. Fixed-dose combinations are designed to simplify the medication regimen and potentially improve compliance. However the data on comparison of fixed-dose combination with free-drug regimen to improve patient's medication compliance is limited. We conducted a MEDLINE search of studies using the words fixed-dose combinations, compliance and/or adherence. The inclusion criteria were studies which involved fixed-dose combination versus free-drug components of the regimen given separately. Only studies which reported patient's compliance were included. Of the 68 studies on fixed-dose combinations, only 9 studies fulfilled the inclusion criteria. Two studies were in patients with tuberculosis, 4 in the hypertensive population, 1 in patients with human immunodeficiency virus (HIV) disease and 2 in the diabetic population. A total of 11,925 patients on fixed-dose combination were compared against 8317 patients on free-drug component regimen. Fixed-dose combination resulted in a 26% decrease in the risk of non-compliance compared with free-drug component regimen (pooled relative risk [RR] 0.74; 95% confidence interval [CI], 0.69-0.80; P <.0001). There was no evidence of heterogeneity in this analysis (chi(2)=14.49, df=8; P=.07). A subgroup analysis of the 4 studies on hypertension showed that fixed-dose combination (pooled RR 0.76; 95% CI, 0.71-0.81; P <.0001) decreased the risk of medication non-compliance by 24% compared with free-drug combination regimen. Fixed-dose combination decreases the risk of medication non-compliance and should be considered in patients with chronic conditions like hypertension for improving medication compliance which can translate into better clinical outcomes.
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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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              Clinical pharmacokinetics of losartan.

              Losartan is the first orally available angiotensin-receptor antagonist without agonist properties. Following oral administration, losartan is rapidly absorbed, reaching maximum concentrations 1-2 hours post-administration. After oral administration approximately 14% of a losartan dose is converted to the pharmacologically active E 3174 metabolite. E 3174 is 10- to 40-fold more potent than its parent compound and its estimated terminal half-life ranges from 6 to 9 hours. The pharmacokinetics of losartan and E 3174 are linear, dose-proportional and do not substantially change with repetitive administration. The recommended dosage of losartan 50 mg/day can be administered without regard to food. There are no clinically significant effects of age, sex or race on the pharmacokinetics of losartan, and no dosage adjustment is necessary in patients with mild hepatic impairment or various degrees of renal insufficiency. Losartan, or its E 3174 metabolite, is not removed during haemodialysis. The major metabolic pathway for losartan is by the cytochrome P450 (CYP) 3A4, 2C9 and 2C10 isoenzymes. Overall, losartan has a favorable drug-drug interaction profile, as evidenced by the lack of clinically relevant interactions between this drug and a range of inhibitors and stimulators of the CYP450 system. Losartan does not have a drug-drug interaction with hydrochlorothiazide, warfarin or digoxin. Losartan should be avoided in pregnancy, as is the case with all other angiotensin-receptor antagonists. When given in the second and third trimester of pregnancy, losartan is often associated with serious fetal toxicity. Losartan is a competitive antagonist that causes a parallel rightward shift of the concentration-contractile response curve to angiotensin-II, while E 3174 is a noncompetitive "insurmountable" antagonist of angiotensin-II. The maximum recommended daily dose of losartan is 100mg, which can be given as a once-daily dose or by splitting the same total daily dose into two doses. Losartan reduces blood pressure comparably to other angiotensin-receptor antagonists. Losartan has been extensively studied relative to end-organ protection, with studies having been conducted in diabetic nephropathy, heart failure, post-myocardial infarction and hypertensive patients with left ventricular hypertrophy. The results of these studies have been sufficiently positive to support a more widespread use of angiotensin-receptor antagonists in the setting of various end-organ diseases. Losartan, like other angiotensin-receptor antagonists, is devoid of significant adverse effects.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                19 February 2020
                2020
                : 14
                : 661-668
                Affiliations
                [1 ]Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital , Seoul, Republic of Korea
                [2 ]Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Republic of Korea
                [3 ]Hanmi Pharm. Co., Ltd ., Seoul, Republic of Korea
                [4 ]Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital , Seongnam, Republic of Korea
                Author notes
                Correspondence: Jae-Yong Chung Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital , 82, Gumi-ro, 173 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do13620, Republic of KoreaTel +82-31-787-3955Fax +82-31-787-4045 Email jychung@snubh.org
                Author information
                http://orcid.org/0000-0002-5281-8811
                http://orcid.org/0000-0002-8302-2488
                http://orcid.org/0000-0002-9982-6560
                http://orcid.org/0000-0002-8384-3139
                http://orcid.org/0000-0003-4188-2786
                Article
                233014
                10.2147/DDDT.S233014
                7036667
                f3504e87-3f07-4f44-8a20-a46efb6d4708
                © 2020 Yoon 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).

                History
                : 30 September 2019
                : 29 January 2020
                Page count
                Figures: 2, Tables: 3, References: 21, Pages: 8
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine
                fixed-dose combination,loose combination,bioequivalence,pharmacokinetics,hypertension,dyslipidemia

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