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      Pharmacokinetics and tolerability of IDP-73152 mesylate after a single oral administration under fasted and fed conditions in healthy volunteers

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          Abstract

          Background and objective

          IDP-73152 mesylate is a peptide deformylase inhibitor under investigation for the treatment of complicated skin and respiratory tract infections. The objective of this study was to investigate the pharmacokinetic (PK) profile and tolerability of IDP-73152 and the effect of food after a single oral administration.

          Methods

          A dose block-randomized, double-blind, placebo-controlled, dose-escalation study was conducted. A total of 56 healthy volunteers received IDP-73152 mesylate in a single oral dose of 40, 80, 160, 320, 640, or 1280 mg in the fasted and fed (640 mg only) states. Blood and urine samples for PK analysis were collected up to 48 h post dose.

          Results

          The area under the plasma concentration-time curve (AUC 0-t) of IDP-73152 increased in a dose-proportional manner in the range of 40–320 mg. The mean terminal half-life decreased from 10.7 to 6.2 hrs as the dose increased. The fraction excreted unchanged in the urine ranged from 0.05 to 0.12. In the 640-mg dose group, food delayed the median time to peak concentration ( t max) from 0.9 to 3.5 hrs. Furthermore, the maximum plasma concentration (C max) were decreased by 36.2%; however, AUC 0-t was not generally affected. No serious adverse event or clinically significant findings were observed.

          Conclusions

          The systemic exposure of IDP-73152 proportionally increased as the dose increased up to 320 mg. The rate of absorption and extent of exposure were reduced by food intake. IDP-73152 was well tolerated without clinically significant adverse effects after a single oral administration.

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          Most cited references 13

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          Drug-induced QT interval prolongation: mechanisms and clinical management.

          The prolonged QT interval is both widely seen and associated with the potentially deadly rhythm, Torsades de Pointes (TdP). While it can occur spontaneously in the congenital form, there is a wide array of drugs that have been implicated in the prolongation of the QT interval. Some of these drugs have either been restricted or withdrawn from the market due to the increased incidence of fatal polymorphic ventricular tachycardia. The list of drugs that cause QT prolongation continues to grow, and an updated list of specific drugs that prolong the QT interval can be found at www.qtdrugs.org. This review focuses on the mechanism of drug-induced QT prolongation, risk factors for TdP, culprit drugs, prevention and monitoring of prolonged drug-induced QT prolongation and treatment strategies.
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            Peptide deformylase as a target for new generation, broad spectrum antimicrobial agents.

            Peptide deformylase was discovered 30 years ago, but as a result of its unusually unstable activity it was not fully characterized until very recently. The aim of this paper is to review the many recent data concerning this enzyme and to try to assess its potential as a target for future antimicrobial drugs.
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              Management of complicated skin and soft tissue infections with a special focus on the role of newer antibiotics

              Complicated skin and soft tissue infections (cSSTIs) represent the severe form of infectious disease that involves deeper soft tissues. Involvement of methicillin-resistant Staphylococcus aureus (MRSA) further complicates cSSTI with increased hospitalization, health care costs, and overall mortality. Various international guidelines provide recommendations on the management of cSSTIs, with the inclusion of newer antibiotics. This literature-based review discusses the overall management of cSSTI, including appropriate use of antibiotics in clinical practice. Successful treatment of cSSTIs starts with early and precise diagnosis, including identification of causative pathogen and its load, determination of infection severity, associated complications, and risk factors. The current standard-of-care for cSSTIs involves incision, drainage, surgical debridement, broad-spectrum antibiotic therapy, and supportive care. In recent years, the emergence of newer antibiotics (eg, ceftaroline, tigecycline, daptomycin, linezolid, etc) has provided clinicians wider options of antimicrobial therapy. Selection of antibiotics should be based on the drug characteristics, effectiveness, safety, and treatment costs, alongside other aspects such as host factors and local multidrug resistance rates. However, larger studies on newer antibiotics are warranted to refine the decision making on the appropriate antimicrobial therapy. Local Antimicrobial Stewardship Program strategies in health care settings could guide clinicians for early initiation of specific treatments to combat region-specific antimicrobial resistance, minimize adverse effects, and to improve outcomes such as reduction in Clostridium difficile infections. These strategies involving iv-to-oral switch, de-escalation to narrow-spectrum antibiotics, and dose optimization have an impact on the overall improvement of cSSTI therapy outcomes, especially in countries like Singapore that has a high disease burden.
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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
                24 July 2019
                2019
                : 13
                : 2483-2490
                Affiliations
                [1 ]Department of Pharmacology, Gachon University College of Medicine , Incheon, Korea
                [2 ]Clinical Trials Center, Gachon University Gil Medical Center , Incheon, Korea
                [3 ]Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital , Seoul, Korea
                [4 ]Department of Clinical Pharmacology and Therapeutics, Kyung Hee University Hospital , Seoul, Korea
                [5 ]East-West Medical Research Institute, Kyung Hee University , Seoul, Korea
                [6 ]Research Laboratories ILDONG Pharmaceutical Co. Ltd , Hwaseong, Korea
                Author notes
                Correspondence: Kyung-Sang YuDepartment of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital , 101 Daehak-ro Jongno-gu, Seoul110-744, KoreaTel +82 22 072 1920Fax +82 2 742 9252Email ksyu@ 123456snu.ac.kr
                Article
                209238
                10.2147/DDDT.S209238
                6664420
                © 2019 Shin 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: 3, Tables: 2, References: 13, Pages: 8
                Categories
                Original Research

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