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      Comparison of the pharmacokinetics and tolerability of HCP1004 (a fixed-dose combination of naproxen and esomeprazole strontium) and VIMOVO ® (a marketed fixed-dose combination of naproxen and esomeprazole magnesium) in healthy volunteers

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          Abstract

          Background

          HCP1004 is a newly developed fixed-dose combination of naproxen (500 mg) and esomeprazole strontium (20 mg) that is used in the treatment of rheumatic diseases and can reduce the risk of nonsteroidal anti-inflammatory drug-associated ulcers. The aim of this study was to evaluate the pharmacokinetics (PK) and safety of HCP1004 compared to VIMOVO ® (a marketed fixed-dose combination of naproxen and esomeprazole magnesium).

          Subjects and methods

          An open-label, randomized, two-treatment, two-sequence crossover, single-dose clinical study was conducted in 70 healthy volunteers. In each period, a reference (VIMOVO ®) or test (HCP1004) drug was administered orally, and serial blood samples for PK analysis were collected up to 72 hours after dosing. To evaluate the PK profiles, the maximum plasma concentration (C max) and the area under the concentration–time curve from 0 to the last measurable time (AUC 0−t) were estimated using a noncompartmental method. Safety profiles were evaluated throughout the study.

          Results

          Sixty-six of the 70 subjects completed the study. The C max (mean ± standard deviation) and AUC 0−t (mean ± standard deviation) for naproxen in HCP1004 were 61.67±15.16 µg/mL and 1,206.52±166.46 h·µg/mL, respectively; in VIMOVO ®; these values were 61.85±14.54 µg/mL and 1,211.44±170.01 h·µg/mL, respectively. The C max and AUC 0−t for esomeprazole in HCP1004 were 658.21±510.91 ng/mL and 1,109.11±1,111.59 h·ng/mL, respectively; for VIMOVO ®, these values were 595.09±364.23 ng/mL and 1,015.12±952.98 h·ng/mL, respectively. The geometric mean ratios and 90% confidence intervals (CIs) (HCP1004 to VIMOVO ®) of the C max and AUC 0−t of naproxen were 0.99 (0.94–1.06) and 1.00 (0.98–1.01), respectively. For esomeprazole, the geometric mean ratios (90% CI) for the C max and AUC 0−t were 0.99 (0.82–1.18) and 1.04 (0.91–1.18), respectively. The overall results of the safety assessment showed no clinically significant issues for either treatment.

          Conclusion

          The PK of HCP1004 500/20 mg was comparable to that of VIMOVO ® 500/20 mg for both naproxen and esomeprazole after a single oral dose. Both drugs were well-tolerated without any safety issues.

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          Most cited references 18

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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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            Pharmacogenetics, pharmacogenomics, and individualized medicine.

            Individual variability in drug efficacy and drug safety is a major challenge in current clinical practice, drug development, and drug regulation. For more than 5 decades, studies of pharmacogenetics have provided ample examples of causal relations between genotypes and drug response to account for phenotypic variations of clinical importance in drug therapy. The convergence of pharmacogenetics and human genomics in recent years has dramatically accelerated the discovery of new genetic variations that potentially underlie variability in drug response, giving birth to pharmacogenomics. In addition to the rapid accumulation of knowledge on genome-disease and genome-drug interactions, there arises the hope of individualized medicine. Here we review recent progress in the understanding of genetic contributions to major individual variability in drug therapy with focus on genetic variations of drug target, drug metabolism, drug transport, disease susceptibility, and drug safety. Challenges to future pharmacogenomics and its translation into individualized medicine, drug development, and regulation are discussed. For example, knowledge on genetic determinants of disease pathogenesis and drug action, especially those of complex disease and drug response, is not always available. Relating the many gene variations from genomic sequencing to clinical phenotypes may not be straightforward. It is often very challenging to conduct large scale, prospective studies to establish causal associations between genetic variations and drug response or to evaluate the utility and cost-effectiveness of genomic medicine. Overcoming the obstacles holds promise for achieving the ultimate goal of effective and safe medication to targeted patients with appropriate genotypes.
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              • Article: not found

              Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future.

              The field of cytochrome P450 pharmacogenetics has progressed rapidly during the past 25 years. All the major human drug-metabolizing P450 enzymes have been identified and cloned, and the major gene variants that cause inter-individual variability in drug response and are related to adverse drug reactions have been identified. This information now provides the basis for the use of predictive pharmacogenetics to yield drug therapies that are more efficient and safer. Today, we understand which drugs warrant dosing based on pharmacogenetics to improve drug treatment. It is anticipated that, in the future, genotyping could be used to personalize drug treatment for vast numbers of subjects, decreasing the cost of drug treatment and increasing the efficacy of drugs and health in general. I estimate that such personalized P450 gene-based treatment would be relevant for 10-20% of all drug therapy.
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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
                31 July 2015
                : 9
                : 4127-4135
                Affiliations
                [1 ]Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
                [2 ]Clinical Trials Center, Gachon University Gil Medical Center, Incheon, Republic of Korea
                [3 ]Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
                Author notes
                Correspondence: Kyung-Sang Yu, Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Republic of Korea, Tel +82 2 2072 1920, Fax +82 2 742 9252, Email ksyu@ 123456snu.ac.kr
                Article
                dddt-9-4127
                10.2147/DDDT.S86725
                4527374
                © 2015 Choi 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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