QT prolongation and proarrhythmia by moxifloxacin: concordance of preclinical models in relation to clinical outcome
Moxifloxacin, a fluoroquinolone antibiotic associated with QT prolongation, has been recommended as a positive control by regulatory authorities to evaluate the sensitivity of both clinical and preclinical studies to detect small but significant increases in QT interval measurements. In this study,...
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| creator | Chen, Xian Cass, Jessica D Bradley, Jenifer A Dahm, Corinn M Sun, Zhuoqian Kadyszewski, Edmund Engwall, Michael J Zhou, Jun |
| description | Moxifloxacin, a fluoroquinolone antibiotic associated with QT prolongation, has been recommended as a positive control by regulatory authorities to evaluate the sensitivity of both clinical and preclinical studies to detect small but significant increases in QT interval measurements.
In this study, we investigated effects of moxifloxacin on the hERG current in HEK‐293 cells, electrocardiograms in conscious telemetered dogs, and repolarization parameters and arrhythmogenic potentials in the arterially perfused rabbit ventricular wedge model.
Moxifloxacin inhibited the hERG current with an IC50 of 35.7 μM. In conscious telemetered dogs, moxifloxacin significantly prolonged QTc at 30 and 90 mg kg−1, with mean serum Cmax of 8.52 and 22.3 μg ml−1, respectively. In the wedge preparation, moxifloxacin produced a concentration‐dependent prolongation of the action potential duration, QT interval, and the time between peak and end of the T wave, an indicator for transmural dispersion of repolarization. Phase 2 early after‐depolarizations were observed in one of five experiments at 30 μM and five of five experiments at 100 μM. The arrhythmogenic potential was also concentration‐dependent, and 100 μM (∼18‐fold above the typical unbound Cmax exposure in clinical usage) appeared to have a high risk of inducing torsade de pointes (TdP).
Our data indicated a good correlation among the concentration–response relationships in the three preclinical models and with the available clinical data. The lack of TdP report by moxifloxacin in patients without other risk factors might be attributable to its well‐behaved pharmacokinetic profile and other dose‐limiting effects.
British Journal of Pharmacology (2005) 146, 792–799. doi:10.1038/sj.bjp.0706389 |
| doi_str_mv | 10.1038/sj.bjp.0706389 |
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In this study, we investigated effects of moxifloxacin on the hERG current in HEK‐293 cells, electrocardiograms in conscious telemetered dogs, and repolarization parameters and arrhythmogenic potentials in the arterially perfused rabbit ventricular wedge model.
Moxifloxacin inhibited the hERG current with an IC50 of 35.7 μM. In conscious telemetered dogs, moxifloxacin significantly prolonged QTc at 30 and 90 mg kg−1, with mean serum Cmax of 8.52 and 22.3 μg ml−1, respectively. In the wedge preparation, moxifloxacin produced a concentration‐dependent prolongation of the action potential duration, QT interval, and the time between peak and end of the T wave, an indicator for transmural dispersion of repolarization. Phase 2 early after‐depolarizations were observed in one of five experiments at 30 μM and five of five experiments at 100 μM. The arrhythmogenic potential was also concentration‐dependent, and 100 μM (∼18‐fold above the typical unbound Cmax exposure in clinical usage) appeared to have a high risk of inducing torsade de pointes (TdP).
Our data indicated a good correlation among the concentration–response relationships in the three preclinical models and with the available clinical data. The lack of TdP report by moxifloxacin in patients without other risk factors might be attributable to its well‐behaved pharmacokinetic profile and other dose‐limiting effects.
British Journal of Pharmacology (2005) 146, 792–799. doi:10.1038/sj.bjp.0706389</description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1038/sj.bjp.0706389</identifier><identifier>PMID: 16158069</identifier><identifier>CODEN: BJPCBM</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Action Potentials - drug effects ; Animals ; Anti-Infective Agents - adverse effects ; Anti-Infective Agents - blood ; Anti-Infective Agents - pharmacokinetics ; Area Under Curve ; arrhythmia ; Arrhythmias, Cardiac - chemically induced ; Arrhythmias, Cardiac - physiopathology ; Aza Compounds - adverse effects ; Aza Compounds - blood ; Aza Compounds - pharmacokinetics ; Biological and medical sciences ; Cardiac dysrhythmias ; Cardiology. Vascular system ; Cell Line ; Disease Models, Animal ; Dogs ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical - methods ; drug safety ; Electrocardiography - drug effects ; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors ; Ether-A-Go-Go Potassium Channels - physiology ; Female ; Fluoroquinolones ; Heart ; hERG ; Humans ; Long QT Syndrome - chemically induced ; Long QT Syndrome - physiopathology ; Male ; Medical sciences ; Moxifloxacin ; Pharmacology. Drug treatments ; Phenethylamines - pharmacology ; Potassium Channels, Inwardly Rectifying - antagonists & inhibitors ; Potassium Channels, Inwardly Rectifying - physiology ; QT interval ; Quinolines - adverse effects ; Quinolines - blood ; Quinolines - pharmacokinetics ; Rabbits ; risk assessment ; Sulfonamides - pharmacology ; Telemetry - methods ; Treatment Outcome</subject><ispartof>British journal of pharmacology, 2005-11, Vol.146 (6), p.792-799</ispartof><rights>2005 British Pharmacological Society</rights><rights>2006 INIST-CNRS</rights><rights>Copyright Nature Publishing Group Nov 2005</rights><rights>Copyright 2005, Nature Publishing Group 2005 Nature Publishing Group</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5559-458647dce1f735bdaa90cc10a5d9c798c223654b85ba10e5049157529d7e0b53</citedby><cites>FETCH-LOGICAL-c5559-458647dce1f735bdaa90cc10a5d9c798c223654b85ba10e5049157529d7e0b53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751220/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751220/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,1411,1427,27901,27902,45550,45551,46384,46808,53766,53768</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17262807$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16158069$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Xian</creatorcontrib><creatorcontrib>Cass, Jessica D</creatorcontrib><creatorcontrib>Bradley, Jenifer A</creatorcontrib><creatorcontrib>Dahm, Corinn M</creatorcontrib><creatorcontrib>Sun, Zhuoqian</creatorcontrib><creatorcontrib>Kadyszewski, Edmund</creatorcontrib><creatorcontrib>Engwall, Michael J</creatorcontrib><creatorcontrib>Zhou, Jun</creatorcontrib><title>QT prolongation and proarrhythmia by moxifloxacin: concordance of preclinical models in relation to clinical outcome</title><title>British journal of pharmacology</title><addtitle>Br J Pharmacol</addtitle><description>Moxifloxacin, a fluoroquinolone antibiotic associated with QT prolongation, has been recommended as a positive control by regulatory authorities to evaluate the sensitivity of both clinical and preclinical studies to detect small but significant increases in QT interval measurements.
In this study, we investigated effects of moxifloxacin on the hERG current in HEK‐293 cells, electrocardiograms in conscious telemetered dogs, and repolarization parameters and arrhythmogenic potentials in the arterially perfused rabbit ventricular wedge model.
Moxifloxacin inhibited the hERG current with an IC50 of 35.7 μM. In conscious telemetered dogs, moxifloxacin significantly prolonged QTc at 30 and 90 mg kg−1, with mean serum Cmax of 8.52 and 22.3 μg ml−1, respectively. In the wedge preparation, moxifloxacin produced a concentration‐dependent prolongation of the action potential duration, QT interval, and the time between peak and end of the T wave, an indicator for transmural dispersion of repolarization. Phase 2 early after‐depolarizations were observed in one of five experiments at 30 μM and five of five experiments at 100 μM. The arrhythmogenic potential was also concentration‐dependent, and 100 μM (∼18‐fold above the typical unbound Cmax exposure in clinical usage) appeared to have a high risk of inducing torsade de pointes (TdP).
Our data indicated a good correlation among the concentration–response relationships in the three preclinical models and with the available clinical data. The lack of TdP report by moxifloxacin in patients without other risk factors might be attributable to its well‐behaved pharmacokinetic profile and other dose‐limiting effects.
British Journal of Pharmacology (2005) 146, 792–799. doi:10.1038/sj.bjp.0706389</description><subject>Action Potentials - drug effects</subject><subject>Animals</subject><subject>Anti-Infective Agents - adverse effects</subject><subject>Anti-Infective Agents - blood</subject><subject>Anti-Infective Agents - pharmacokinetics</subject><subject>Area Under Curve</subject><subject>arrhythmia</subject><subject>Arrhythmias, Cardiac - chemically induced</subject><subject>Arrhythmias, Cardiac - physiopathology</subject><subject>Aza Compounds - adverse effects</subject><subject>Aza Compounds - blood</subject><subject>Aza Compounds - pharmacokinetics</subject><subject>Biological and medical sciences</subject><subject>Cardiac dysrhythmias</subject><subject>Cardiology. Vascular system</subject><subject>Cell Line</subject><subject>Disease Models, Animal</subject><subject>Dogs</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Evaluation, Preclinical - methods</subject><subject>drug safety</subject><subject>Electrocardiography - drug effects</subject><subject>Ether-A-Go-Go Potassium Channels - antagonists & inhibitors</subject><subject>Ether-A-Go-Go Potassium Channels - physiology</subject><subject>Female</subject><subject>Fluoroquinolones</subject><subject>Heart</subject><subject>hERG</subject><subject>Humans</subject><subject>Long QT Syndrome - chemically induced</subject><subject>Long QT Syndrome - physiopathology</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Moxifloxacin</subject><subject>Pharmacology. Drug treatments</subject><subject>Phenethylamines - pharmacology</subject><subject>Potassium Channels, Inwardly Rectifying - antagonists & inhibitors</subject><subject>Potassium Channels, Inwardly Rectifying - physiology</subject><subject>QT interval</subject><subject>Quinolines - adverse effects</subject><subject>Quinolines - blood</subject><subject>Quinolines - pharmacokinetics</subject><subject>Rabbits</subject><subject>risk assessment</subject><subject>Sulfonamides - pharmacology</subject><subject>Telemetry - methods</subject><subject>Treatment Outcome</subject><issn>0007-1188</issn><issn>1476-5381</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqFkUFv1DAQhS1ERZfClSOykDhmGTtxbHNAohVtkSoVpL1bjuN0HTn2Ymdp99_jaqMWTpxGmvfNm9E8hN4RWBOoxac8rrtxtwYObS3kC7QiDW8rVgvyEq0AgFeECHGKXuc8AhSRs1folLSECWjlCs0_N3iXoo_hTs8uBqxD_9jQKW0P83ZyGncHPMUHN_j4oI0Ln7GJwcTU62AsjkOhrfEuOKN9AXvrM3YBJ-uPhnPET3LczyZO9g06GbTP9u1Sz9Dm8tvm4rq6ub36fvH1pjKMMVk1TLQN740lA69Z12stwRgCmvXScCkMpXXLmk6wThOwDBpJGGdU9txCx-oz9OVou9t3ky0-YU7aq11yk04HFbVT_yrBbdVd_K0IZ4RSKAYfFoMUf-1tntUY9ymUkxUlnAIhjSzQ-giZFHNOdnhaQEA9ZqTyqEpGasmoDLz_-6xnfAmlAB8XQOfytSGVT7v8zHHaUgG8cPWRu3feHv6zVp3_uKaNlPUfxICtzw</recordid><startdate>200511</startdate><enddate>200511</enddate><creator>Chen, Xian</creator><creator>Cass, Jessica D</creator><creator>Bradley, Jenifer A</creator><creator>Dahm, Corinn M</creator><creator>Sun, Zhuoqian</creator><creator>Kadyszewski, Edmund</creator><creator>Engwall, Michael J</creator><creator>Zhou, Jun</creator><general>Blackwell Publishing Ltd</general><general>Nature Publishing</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7RV</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope></search><sort><creationdate>200511</creationdate><title>QT prolongation and proarrhythmia by moxifloxacin: concordance of preclinical models in relation to clinical outcome</title><author>Chen, Xian ; Cass, Jessica D ; Bradley, Jenifer A ; Dahm, Corinn M ; Sun, Zhuoqian ; Kadyszewski, Edmund ; Engwall, Michael J ; Zhou, Jun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5559-458647dce1f735bdaa90cc10a5d9c798c223654b85ba10e5049157529d7e0b53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Action Potentials - drug effects</topic><topic>Animals</topic><topic>Anti-Infective Agents - adverse effects</topic><topic>Anti-Infective Agents - blood</topic><topic>Anti-Infective Agents - pharmacokinetics</topic><topic>Area Under Curve</topic><topic>arrhythmia</topic><topic>Arrhythmias, Cardiac - chemically induced</topic><topic>Arrhythmias, Cardiac - physiopathology</topic><topic>Aza Compounds - adverse effects</topic><topic>Aza Compounds - blood</topic><topic>Aza Compounds - pharmacokinetics</topic><topic>Biological and medical sciences</topic><topic>Cardiac dysrhythmias</topic><topic>Cardiology. Vascular system</topic><topic>Cell Line</topic><topic>Disease Models, Animal</topic><topic>Dogs</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Evaluation, Preclinical - methods</topic><topic>drug safety</topic><topic>Electrocardiography - drug effects</topic><topic>Ether-A-Go-Go Potassium Channels - antagonists & inhibitors</topic><topic>Ether-A-Go-Go Potassium Channels - physiology</topic><topic>Female</topic><topic>Fluoroquinolones</topic><topic>Heart</topic><topic>hERG</topic><topic>Humans</topic><topic>Long QT Syndrome - chemically induced</topic><topic>Long QT Syndrome - physiopathology</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Moxifloxacin</topic><topic>Pharmacology. Drug treatments</topic><topic>Phenethylamines - pharmacology</topic><topic>Potassium Channels, Inwardly Rectifying - antagonists & inhibitors</topic><topic>Potassium Channels, Inwardly Rectifying - physiology</topic><topic>QT interval</topic><topic>Quinolines - adverse effects</topic><topic>Quinolines - blood</topic><topic>Quinolines - pharmacokinetics</topic><topic>Rabbits</topic><topic>risk assessment</topic><topic>Sulfonamides - pharmacology</topic><topic>Telemetry - methods</topic><topic>Treatment Outcome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Xian</creatorcontrib><creatorcontrib>Cass, Jessica D</creatorcontrib><creatorcontrib>Bradley, Jenifer A</creatorcontrib><creatorcontrib>Dahm, Corinn M</creatorcontrib><creatorcontrib>Sun, Zhuoqian</creatorcontrib><creatorcontrib>Kadyszewski, Edmund</creatorcontrib><creatorcontrib>Engwall, Michael J</creatorcontrib><creatorcontrib>Zhou, Jun</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Xian</au><au>Cass, Jessica D</au><au>Bradley, Jenifer A</au><au>Dahm, Corinn M</au><au>Sun, Zhuoqian</au><au>Kadyszewski, Edmund</au><au>Engwall, Michael J</au><au>Zhou, Jun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>QT prolongation and proarrhythmia by moxifloxacin: concordance of preclinical models in relation to clinical outcome</atitle><jtitle>British journal of pharmacology</jtitle><addtitle>Br J Pharmacol</addtitle><date>2005-11</date><risdate>2005</risdate><volume>146</volume><issue>6</issue><spage>792</spage><epage>799</epage><pages>792-799</pages><issn>0007-1188</issn><eissn>1476-5381</eissn><coden>BJPCBM</coden><abstract>Moxifloxacin, a fluoroquinolone antibiotic associated with QT prolongation, has been recommended as a positive control by regulatory authorities to evaluate the sensitivity of both clinical and preclinical studies to detect small but significant increases in QT interval measurements.
In this study, we investigated effects of moxifloxacin on the hERG current in HEK‐293 cells, electrocardiograms in conscious telemetered dogs, and repolarization parameters and arrhythmogenic potentials in the arterially perfused rabbit ventricular wedge model.
Moxifloxacin inhibited the hERG current with an IC50 of 35.7 μM. In conscious telemetered dogs, moxifloxacin significantly prolonged QTc at 30 and 90 mg kg−1, with mean serum Cmax of 8.52 and 22.3 μg ml−1, respectively. In the wedge preparation, moxifloxacin produced a concentration‐dependent prolongation of the action potential duration, QT interval, and the time between peak and end of the T wave, an indicator for transmural dispersion of repolarization. Phase 2 early after‐depolarizations were observed in one of five experiments at 30 μM and five of five experiments at 100 μM. The arrhythmogenic potential was also concentration‐dependent, and 100 μM (∼18‐fold above the typical unbound Cmax exposure in clinical usage) appeared to have a high risk of inducing torsade de pointes (TdP).
Our data indicated a good correlation among the concentration–response relationships in the three preclinical models and with the available clinical data. The lack of TdP report by moxifloxacin in patients without other risk factors might be attributable to its well‐behaved pharmacokinetic profile and other dose‐limiting effects.
British Journal of Pharmacology (2005) 146, 792–799. doi:10.1038/sj.bjp.0706389</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>16158069</pmid><doi>10.1038/sj.bjp.0706389</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Action Potentials - drug effects Animals Anti-Infective Agents - adverse effects Anti-Infective Agents - blood Anti-Infective Agents - pharmacokinetics Area Under Curve arrhythmia Arrhythmias, Cardiac - chemically induced Arrhythmias, Cardiac - physiopathology Aza Compounds - adverse effects Aza Compounds - blood Aza Compounds - pharmacokinetics Biological and medical sciences Cardiac dysrhythmias Cardiology. Vascular system Cell Line Disease Models, Animal Dogs Dose-Response Relationship, Drug Drug Evaluation, Preclinical - methods drug safety Electrocardiography - drug effects Ether-A-Go-Go Potassium Channels - antagonists & inhibitors Ether-A-Go-Go Potassium Channels - physiology Female Fluoroquinolones Heart hERG Humans Long QT Syndrome - chemically induced Long QT Syndrome - physiopathology Male Medical sciences Moxifloxacin Pharmacology. Drug treatments Phenethylamines - pharmacology Potassium Channels, Inwardly Rectifying - antagonists & inhibitors Potassium Channels, Inwardly Rectifying - physiology QT interval Quinolines - adverse effects Quinolines - blood Quinolines - pharmacokinetics Rabbits risk assessment Sulfonamides - pharmacology Telemetry - methods Treatment Outcome |
| title | QT prolongation and proarrhythmia by moxifloxacin: concordance of preclinical models in relation to clinical outcome |
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