Population pharmacokinetic–pharmacodynamic analysis of vernakalant hydrochloride injection (RSD1235) in atrial fibrillation or atrial flutter
Vernakalant hydrochloride is a novel, relatively atrial-selective antiarrhythmic agent that rapidly converts atrial fibrillation (AF) to sinus rhythm (SR). This analysis integrates pharmacokinetic (PK) and safety data from 5 clinical trials of patients with AF or atrial flutter (AFL). Patients were...
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| Veröffentlicht in: | Journal of pharmacokinetics and pharmacodynamics 2011-10, Vol.38 (5), p.541-562 |
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| creator | Mao, Zhongping Wheeler, Jeff J. Townsend, Robert Gao, Yuying Kshirsagar, Smita Keirns, James J. |
| description | Vernakalant hydrochloride is a novel, relatively atrial-selective antiarrhythmic agent that rapidly converts atrial fibrillation (AF) to sinus rhythm (SR). This analysis integrates pharmacokinetic (PK) and safety data from 5 clinical trials of patients with AF or atrial flutter (AFL). Patients were initially given a 10-min intravenous (IV) infusion of vernakalant 3 mg/kg or placebo. If SR was not evident after a 15-min observation, then a second 10-min IV infusion of vernakalant 2 mg/kg or placebo was given. Population pharmacokinetic/pharmacodynamic (PK/PD) models were constructed for QT interval prolongation corrected for heart rate by Fridericia’s formula (QTcF) and for changes in systolic blood pressure (SBP). The exposure–response relationships for QTcF and SBP were best described by sigmoidal maximum-effect (
E
max
) models. For QTcF, the model was characterized by a typical
E
max
of 20.3 ms, and by a vernakalant median effective concentration dependent (
EC
50
) on conversion status (4,222 ng/ml for patients converting to SR and 2,276 ng/ml for those remaining in AF/AFL). For SBP, the model was characterized by
E
max
of 3.05 mmHg and
EC
50
of 1,141 ng/ml. Risk of hypotension (SBP |
| doi_str_mv | 10.1007/s10928-011-9207-3 |
| format | Article |
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E
max
) models. For QTcF, the model was characterized by a typical
E
max
of 20.3 ms, and by a vernakalant median effective concentration dependent (
EC
50
) on conversion status (4,222 ng/ml for patients converting to SR and 2,276 ng/ml for those remaining in AF/AFL). For SBP, the model was characterized by
E
max
of 3.05 mmHg and
EC
50
of 1,141 ng/ml. Risk of hypotension (SBP <90 mmHg) was primarily associated with low baseline SBP and to a smaller extent with a history of congestive heart failure (CHF); plasma vernakalant concentrations showed a small contribution to the risk of hypotension (relative risk = 1.4 at 4,000 ng/ml), which may be significant with a baseline SBP of <105 mmHg. These results show that vernakalant had a smaller effect on QTcF in patients who demonstrated conversion to SR than those remaining in AF or AFL, and it had a relatively small effect on SBP.</description><identifier>ISSN: 1567-567X</identifier><identifier>EISSN: 1573-8744</identifier><identifier>DOI: 10.1007/s10928-011-9207-3</identifier><identifier>PMID: 21786177</identifier><language>eng</language><publisher>Boston: Springer US</publisher><subject>Anisoles - administration & dosage ; Anisoles - adverse effects ; Anisoles - pharmacokinetics ; Anisoles - pharmacology ; Anti-Arrhythmia Agents - administration & dosage ; Anti-Arrhythmia Agents - adverse effects ; Anti-Arrhythmia Agents - pharmacokinetics ; Anti-Arrhythmia Agents - pharmacology ; Atrial Fibrillation - drug therapy ; Atrial Fibrillation - metabolism ; Atrial Fibrillation - physiopathology ; Atrial Flutter - drug therapy ; Atrial Flutter - metabolism ; Atrial Flutter - physiopathology ; Biochemistry ; Biomedical and Life Sciences ; Biomedical Engineering and Bioengineering ; Biomedicine ; Blood Pressure - drug effects ; Computer Simulation ; Cytochrome P-450 CYP2D6 - metabolism ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Administration Schedule ; Electrocardiography ; Female ; Heart Failure - complications ; Humans ; Hypotension - chemically induced ; Hypotension - metabolism ; Infusions, Intravenous ; Male ; Middle Aged ; Pharmacology/Toxicology ; Pharmacy ; Pyrrolidines - administration & dosage ; Pyrrolidines - adverse effects ; Pyrrolidines - pharmacokinetics ; Pyrrolidines - pharmacology ; Veterinary Medicine/Veterinary Science</subject><ispartof>Journal of pharmacokinetics and pharmacodynamics, 2011-10, Vol.38 (5), p.541-562</ispartof><rights>Springer Science+Business Media, LLC 2011</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c370t-267bfcc79147d578b502ee9cdf985c5e2247125c69c768c492c008e48003125f3</citedby><cites>FETCH-LOGICAL-c370t-267bfcc79147d578b502ee9cdf985c5e2247125c69c768c492c008e48003125f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10928-011-9207-3$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10928-011-9207-3$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21786177$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mao, Zhongping</creatorcontrib><creatorcontrib>Wheeler, Jeff J.</creatorcontrib><creatorcontrib>Townsend, Robert</creatorcontrib><creatorcontrib>Gao, Yuying</creatorcontrib><creatorcontrib>Kshirsagar, Smita</creatorcontrib><creatorcontrib>Keirns, James J.</creatorcontrib><title>Population pharmacokinetic–pharmacodynamic analysis of vernakalant hydrochloride injection (RSD1235) in atrial fibrillation or atrial flutter</title><title>Journal of pharmacokinetics and pharmacodynamics</title><addtitle>J Pharmacokinet Pharmacodyn</addtitle><addtitle>J Pharmacokinet Pharmacodyn</addtitle><description>Vernakalant hydrochloride is a novel, relatively atrial-selective antiarrhythmic agent that rapidly converts atrial fibrillation (AF) to sinus rhythm (SR). This analysis integrates pharmacokinetic (PK) and safety data from 5 clinical trials of patients with AF or atrial flutter (AFL). Patients were initially given a 10-min intravenous (IV) infusion of vernakalant 3 mg/kg or placebo. If SR was not evident after a 15-min observation, then a second 10-min IV infusion of vernakalant 2 mg/kg or placebo was given. Population pharmacokinetic/pharmacodynamic (PK/PD) models were constructed for QT interval prolongation corrected for heart rate by Fridericia’s formula (QTcF) and for changes in systolic blood pressure (SBP). The exposure–response relationships for QTcF and SBP were best described by sigmoidal maximum-effect (
E
max
) models. For QTcF, the model was characterized by a typical
E
max
of 20.3 ms, and by a vernakalant median effective concentration dependent (
EC
50
) on conversion status (4,222 ng/ml for patients converting to SR and 2,276 ng/ml for those remaining in AF/AFL). For SBP, the model was characterized by
E
max
of 3.05 mmHg and
EC
50
of 1,141 ng/ml. Risk of hypotension (SBP <90 mmHg) was primarily associated with low baseline SBP and to a smaller extent with a history of congestive heart failure (CHF); plasma vernakalant concentrations showed a small contribution to the risk of hypotension (relative risk = 1.4 at 4,000 ng/ml), which may be significant with a baseline SBP of <105 mmHg. These results show that vernakalant had a smaller effect on QTcF in patients who demonstrated conversion to SR than those remaining in AF or AFL, and it had a relatively small effect on SBP.</description><subject>Anisoles - administration & dosage</subject><subject>Anisoles - adverse effects</subject><subject>Anisoles - pharmacokinetics</subject><subject>Anisoles - pharmacology</subject><subject>Anti-Arrhythmia Agents - administration & dosage</subject><subject>Anti-Arrhythmia Agents - adverse effects</subject><subject>Anti-Arrhythmia Agents - pharmacokinetics</subject><subject>Anti-Arrhythmia Agents - pharmacology</subject><subject>Atrial Fibrillation - drug therapy</subject><subject>Atrial Fibrillation - metabolism</subject><subject>Atrial Fibrillation - physiopathology</subject><subject>Atrial Flutter - drug therapy</subject><subject>Atrial Flutter - metabolism</subject><subject>Atrial Flutter - physiopathology</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedical Engineering and Bioengineering</subject><subject>Biomedicine</subject><subject>Blood Pressure - drug effects</subject><subject>Computer Simulation</subject><subject>Cytochrome P-450 CYP2D6 - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Double-Blind Method</subject><subject>Drug Administration Schedule</subject><subject>Electrocardiography</subject><subject>Female</subject><subject>Heart Failure - complications</subject><subject>Humans</subject><subject>Hypotension - chemically induced</subject><subject>Hypotension - metabolism</subject><subject>Infusions, Intravenous</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Pharmacology/Toxicology</subject><subject>Pharmacy</subject><subject>Pyrrolidines - administration & dosage</subject><subject>Pyrrolidines - adverse effects</subject><subject>Pyrrolidines - pharmacokinetics</subject><subject>Pyrrolidines - pharmacology</subject><subject>Veterinary Medicine/Veterinary Science</subject><issn>1567-567X</issn><issn>1573-8744</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1UU2P0zAQtdCuaCn8AC4o4gSHLB4nju0jKp9SJRAfEjfLcRzq1om7doKUG_-Aw_7D_SW4pFtOexjN6M2bN5p5CD0FfAUYs1cRsCA8xwC5IJjlxQO0BMqKnLOyvDjWFctT_FigRzHuMIaKEvwQLQgwXgFjS_Tnsz-MTg3W99lhq0KntN_b3gxW3_6-uUOaqVed1ZnqlZuijZlvs18m9GqvnOqHbDs1weut88E2JrP9zuh_ii--fH0DpKAvE5apIVjlstbWwbrTSh_OsBuHwYTH6LJVLponp7xC39-9_bb-kG8-vf-4fr3JdcHwkJOK1a3WTEDJGsp4TTExRuimFZxqaggpGRCqK6FZxXUpiMaYm5JjXCS8LVbo-ax7CP56NHGQOz-mg1yUnAsQQAUkEswkHXyMwbTyEGynwiQBy6MDcnZAJgfk0QFZpJlnJ-Gx7kxznrh7eSKQmRBTq_9pwv_N96v-BWBvlDI</recordid><startdate>20111001</startdate><enddate>20111001</enddate><creator>Mao, Zhongping</creator><creator>Wheeler, Jeff J.</creator><creator>Townsend, Robert</creator><creator>Gao, Yuying</creator><creator>Kshirsagar, Smita</creator><creator>Keirns, James J.</creator><general>Springer US</general><general>Springer Nature B.V</general><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>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope></search><sort><creationdate>20111001</creationdate><title>Population pharmacokinetic–pharmacodynamic analysis of vernakalant hydrochloride injection (RSD1235) in atrial fibrillation or atrial flutter</title><author>Mao, Zhongping ; Wheeler, Jeff J. ; Townsend, Robert ; Gao, Yuying ; Kshirsagar, Smita ; Keirns, James J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c370t-267bfcc79147d578b502ee9cdf985c5e2247125c69c768c492c008e48003125f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Anisoles - administration & dosage</topic><topic>Anisoles - adverse effects</topic><topic>Anisoles - pharmacokinetics</topic><topic>Anisoles - pharmacology</topic><topic>Anti-Arrhythmia Agents - administration & dosage</topic><topic>Anti-Arrhythmia Agents - adverse effects</topic><topic>Anti-Arrhythmia Agents - pharmacokinetics</topic><topic>Anti-Arrhythmia Agents - pharmacology</topic><topic>Atrial Fibrillation - drug therapy</topic><topic>Atrial Fibrillation - metabolism</topic><topic>Atrial Fibrillation - physiopathology</topic><topic>Atrial Flutter - drug therapy</topic><topic>Atrial Flutter - metabolism</topic><topic>Atrial Flutter - physiopathology</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedical Engineering and Bioengineering</topic><topic>Biomedicine</topic><topic>Blood Pressure - drug effects</topic><topic>Computer Simulation</topic><topic>Cytochrome P-450 CYP2D6 - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Double-Blind Method</topic><topic>Drug Administration Schedule</topic><topic>Electrocardiography</topic><topic>Female</topic><topic>Heart Failure - complications</topic><topic>Humans</topic><topic>Hypotension - chemically induced</topic><topic>Hypotension - metabolism</topic><topic>Infusions, Intravenous</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Pharmacology/Toxicology</topic><topic>Pharmacy</topic><topic>Pyrrolidines - administration & dosage</topic><topic>Pyrrolidines - adverse effects</topic><topic>Pyrrolidines - pharmacokinetics</topic><topic>Pyrrolidines - pharmacology</topic><topic>Veterinary Medicine/Veterinary Science</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mao, Zhongping</creatorcontrib><creatorcontrib>Wheeler, Jeff J.</creatorcontrib><creatorcontrib>Townsend, Robert</creatorcontrib><creatorcontrib>Gao, Yuying</creatorcontrib><creatorcontrib>Kshirsagar, Smita</creatorcontrib><creatorcontrib>Keirns, James J.</creatorcontrib><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>Virology and AIDS 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>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</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</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><jtitle>Journal of pharmacokinetics and pharmacodynamics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mao, Zhongping</au><au>Wheeler, Jeff J.</au><au>Townsend, Robert</au><au>Gao, Yuying</au><au>Kshirsagar, Smita</au><au>Keirns, James J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Population pharmacokinetic–pharmacodynamic analysis of vernakalant hydrochloride injection (RSD1235) in atrial fibrillation or atrial flutter</atitle><jtitle>Journal of pharmacokinetics and pharmacodynamics</jtitle><stitle>J Pharmacokinet Pharmacodyn</stitle><addtitle>J Pharmacokinet Pharmacodyn</addtitle><date>2011-10-01</date><risdate>2011</risdate><volume>38</volume><issue>5</issue><spage>541</spage><epage>562</epage><pages>541-562</pages><issn>1567-567X</issn><eissn>1573-8744</eissn><abstract>Vernakalant hydrochloride is a novel, relatively atrial-selective antiarrhythmic agent that rapidly converts atrial fibrillation (AF) to sinus rhythm (SR). This analysis integrates pharmacokinetic (PK) and safety data from 5 clinical trials of patients with AF or atrial flutter (AFL). Patients were initially given a 10-min intravenous (IV) infusion of vernakalant 3 mg/kg or placebo. If SR was not evident after a 15-min observation, then a second 10-min IV infusion of vernakalant 2 mg/kg or placebo was given. Population pharmacokinetic/pharmacodynamic (PK/PD) models were constructed for QT interval prolongation corrected for heart rate by Fridericia’s formula (QTcF) and for changes in systolic blood pressure (SBP). The exposure–response relationships for QTcF and SBP were best described by sigmoidal maximum-effect (
E
max
) models. For QTcF, the model was characterized by a typical
E
max
of 20.3 ms, and by a vernakalant median effective concentration dependent (
EC
50
) on conversion status (4,222 ng/ml for patients converting to SR and 2,276 ng/ml for those remaining in AF/AFL). For SBP, the model was characterized by
E
max
of 3.05 mmHg and
EC
50
of 1,141 ng/ml. Risk of hypotension (SBP <90 mmHg) was primarily associated with low baseline SBP and to a smaller extent with a history of congestive heart failure (CHF); plasma vernakalant concentrations showed a small contribution to the risk of hypotension (relative risk = 1.4 at 4,000 ng/ml), which may be significant with a baseline SBP of <105 mmHg. These results show that vernakalant had a smaller effect on QTcF in patients who demonstrated conversion to SR than those remaining in AF or AFL, and it had a relatively small effect on SBP.</abstract><cop>Boston</cop><pub>Springer US</pub><pmid>21786177</pmid><doi>10.1007/s10928-011-9207-3</doi><tpages>22</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1567-567X |
| ispartof | Journal of pharmacokinetics and pharmacodynamics, 2011-10, Vol.38 (5), p.541-562 |
| issn | 1567-567X 1573-8744 |
| language | eng |
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| subjects | Anisoles - administration & dosage Anisoles - adverse effects Anisoles - pharmacokinetics Anisoles - pharmacology Anti-Arrhythmia Agents - administration & dosage Anti-Arrhythmia Agents - adverse effects Anti-Arrhythmia Agents - pharmacokinetics Anti-Arrhythmia Agents - pharmacology Atrial Fibrillation - drug therapy Atrial Fibrillation - metabolism Atrial Fibrillation - physiopathology Atrial Flutter - drug therapy Atrial Flutter - metabolism Atrial Flutter - physiopathology Biochemistry Biomedical and Life Sciences Biomedical Engineering and Bioengineering Biomedicine Blood Pressure - drug effects Computer Simulation Cytochrome P-450 CYP2D6 - metabolism Dose-Response Relationship, Drug Double-Blind Method Drug Administration Schedule Electrocardiography Female Heart Failure - complications Humans Hypotension - chemically induced Hypotension - metabolism Infusions, Intravenous Male Middle Aged Pharmacology/Toxicology Pharmacy Pyrrolidines - administration & dosage Pyrrolidines - adverse effects Pyrrolidines - pharmacokinetics Pyrrolidines - pharmacology Veterinary Medicine/Veterinary Science |
| title | Population pharmacokinetic–pharmacodynamic analysis of vernakalant hydrochloride injection (RSD1235) in atrial fibrillation or atrial flutter |
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