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      Bioequivalence evaluation of two amlodipine salts, besylate and orotate, each in a fixed-dose combination with olmesartan in healthy subjects

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          Abstract

          A fixed-dose combination of amlodipine and olmesartan is used to treat high blood pressure in patients whose hypertension is not sufficiently controlled with either drug alone. The objective of this study was to evaluate the bioequivalence of two fixed-dose combinations, ie, amlodipine orotate/olmesartan medoxomil 10/40 mg and amlodipine besylate/olmesartan medoxomil 10/40 mg, in healthy subjects. A randomized, open-label, single-dose, two-sequence, two-period, crossover study was conducted in 30 healthy adult volunteers. Blood samples were collected for up to 72 hours post-dose in each period. Safety data included the results of physical examinations, clinical laboratory tests, vital signs, an electrocardiogram, and adverse events. For both amlodipine and olmesartan, the 90% confidence intervals for the geometric mean ratios of AUC last and time to peak plasma concentration fell within the bioequivalence acceptance criteria. The two fixed-dose combinations showed similar safety profiles. Amlodipine orotate/olmesartan medoxomil 10/40 mg was bioequivalent to amlodipine besylate/olmesartan medoxomil 10/40 mg.

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          Most cited references 20

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          International union of pharmacology. XXIII. The angiotensin II receptors.

          The cardiovascular and other actions of angiotensin II (Ang II) are mediated by AT(1) and AT(2) receptors, which are seven transmembrane glycoproteins with 30% sequence similarity. Most species express a single autosomal AT(1) gene, but two related AT(1A) and AT(1B) receptor genes are expressed in rodents. AT(1) receptors are predominantly coupled to G(q/11), and signal through phospholipases A, C, D, inositol phosphates, calcium channels, and a variety of serine/threonine and tyrosine kinases. Many AT(1)-induced growth responses are mediated by transactivation of growth factor receptors. The receptor binding sites for agonist and nonpeptide antagonist ligands have been defined. The latter compounds are as effective as angiotensin converting enzyme inhibitors in cardiovascular diseases but are better tolerated. The AT(2) receptor is expressed at high density during fetal development. It is much less abundant in adult tissues and is up-regulated in pathological conditions. Its signaling pathways include serine and tyrosine phosphatases, phospholipase A(2), nitric oxide, and cyclic guanosine monophosphate. The AT(2) receptor counteracts several of the growth responses initiated by the AT(1) and growth factor receptors. The AT(4) receptor specifically binds Ang IV (Ang 3-8), and is located in brain and kidney. Its signaling mechanisms are unknown, but it influences local blood flow and is associated with cognitive processes and sensory and motor functions. Although AT(1) receptors mediate most of the known actions of Ang II, the AT(2) receptor contributes to the regulation of blood pressure and renal function. The development of specific nonpeptide receptor antagonists has led to major advances in the physiology, pharmacology, and therapy of the renin-angiotensin system.
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            Bioequivalence and other unresolved issues in generic drug substitution.

            Substitution of generic drugs for brand-name products is highly controversial and often is met with suspicion by health care providers and patients. Historically, the debate has focused on the issue of bioequivalence, and clinical practice has identified a number of drug classes for which generic substitution should be approached with caution. Current bioequivalence requirements are based on a measure of average bioequivalence; however, there are fears that use of this measure may be inappropriate in the case of a drug with a narrow or wide therapeutic range or high intrasubject or intersubject variability. Under these circumstances, measures of individual and population bioequivalence are proposed to be more accurate than measures of average bioequivalence. This paper addresses issues of bioequivalence and other concerns with generic drug substitution. I conducted a MEDLINE search of the English-language literature containing the key terms generic, multisource, quality, and brand and published between 1973 and 2003. The names of branded pharmaceuticals whose patents had recently expired (eg, Ventolin HFA, Adalat, Capoten, Tagamet HB 200, and Valium) also were used to search for articles on generic substitution. Reference lists of relevant articles also were searched. Bioequivalence issues are presented together with more general concerns over generic drug substitution, such as consumer perception of risk, differences in product and packaging appearance, and differences in excipients. The literature reviewed act to highlight a number of different drug categories and patient subpopulations for which generic substitution can still prove to be problematic. I recommend that health care providers continue to exercise caution in the consideration of generic drug substitution under certain circumstances.
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              Effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of amlodipine in healthy Korean subjects.

              1,4-Dihydropyridine calcium channel blockers, including amlodipine, are mainly metabolized by cytochrome P450 (CYP) 3A. We investigated the effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of amlodipine in healthy Korean male subjects. Forty healthy male participants were enrolled and genotyped for the CYP3A5*3 gene. Each subject ingested a 5-mg dose of amlodipine, and plasma amlodipine concentrations were measured for 144 hours after dosing. Blood pressure and pulse rate were also measured for pharmacodynamic analysis. Among the 40 volunteers, 24 were CYP3A5*3/*3 carriers and 16 were CYP3A5*1 carriers (CYP3A5*1/*1 in 2 and CYP3A5*1/*3 in 14). The difference in the oral clearance of amlodipine approached statistical significance between the 2 major genotype groups, with CYP3A5*1 carriers (27.0 +/- 8.2 L/h) showing 20% lower clearance than CYP3A5*3/*3 carriers (32.4 +/- 10.2 L/h) (P = .063). However, the mean area under the plasma concentration-time curve of amlodipine was 200.9 +/- 61.9 ng . h/mL for CYP3A5*1 carriers and 167.6 +/- 45.0 ng . h/mL for CYP3A5*3/*3 carriers (P = .029). Moreover, the peak plasma concentration was significantly higher in CYP3A5*1 carriers (3.8 +/- 1.1 ng/mL) than in CYP3A5*3/*3 carriers (3.1 +/- 0.8 ng/mL) (P = .037). Pharmacodynamically, blood pressure and pulse rate were not significantly different between the 2 groups. CYP3A5*3/*3 carriers exhibited lower plasma amlodipine concentrations than CYP3A5*1 carriers. These findings suggest that the polymorphic CYP3A5 gene affects the disposition of amlodipine and provides a plausible explanation for interindividual variability in amlodipine disposition.
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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
                2015
                02 June 2015
                : 9
                : 2811-2817
                Affiliations
                [1 ]Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea
                [2 ]Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Seoul, Republic of Korea
                [3 ]Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea
                [4 ]Department of Clinical Pharmacology, Inje University, Busan Paik Hospital, Busan, Republic of Korea
                [5 ]Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
                [6 ]Dong-A ST Co., Ltd., Seoul, Republic of Korea
                Author notes
                Correspondence: Jae-Wook Ko, Department of Clinical Pharmacology and Therapeutics, 9th Floor, Main Building, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul, Republic of Korea 135-710, Tel +82 2 3410 3690, Fax +82 2 3410 0915, Email jw0701.ko@ 123456samsung.com
                Article
                dddt-9-2811
                10.2147/DDDT.S82820
                4459635
                © 2015 Lee et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. 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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