Quantitative approach for cardiac risk assessment and interpretation in tuberculosis drug development

2018
journal article
article
18
dc.abstract.enCardiotoxicity is among the top drug safety concerns, and is of specific interest in tuberculosis, where this is a known or potential adverse event of current and emerging treatment regimens. As there is a need for a tool, beyond the QT interval, to quantify cardiotoxicity early in drug development, an empirical decision tree based classifier was developed to predict the risk of Torsades de pointes (TdP). The cardiac risk algorithm was developed using pseudo-electrocardiogram (ECG) outputs derived from cardiac myocyte electromechanical model simulations of increasing concentrations of 96 reference compounds which represented a range of clinical TdP risk. The algorithm correctly classified 89% of reference compounds with moderate sensitivity and high specificity (71 and 96%, respectively) as well as 10 out of 12 external validation compounds and the anti-TB drugs moxifloxacin and bedaquiline. The cardiac risk algorithm is suitable to help inform early drug development decisions in TB and will evolve with the addition of emerging data.pl
dc.affiliationWydział Farmaceutyczny : Zakład Farmacji Społecznejpl
dc.cm.date2020-01-07
dc.cm.id88552
dc.contributor.authorPolak, Sebastian - 133197 pl
dc.contributor.authorRomero, Klauspl
dc.contributor.authorBerg, Alexanderpl
dc.contributor.authorPatel, Nikunjkumarpl
dc.contributor.authorJamei, Masoudpl
dc.contributor.authorHermann, Davidpl
dc.contributor.authorHanna, Debrapl
dc.date.accessioned2020-01-17T09:58:42Z
dc.date.available2020-01-17T09:58:42Z
dc.date.issued2018pl
dc.date.openaccess0
dc.description.accesstimew momencie opublikowania
dc.description.number3pl
dc.description.physical457-467pl
dc.description.points25pl
dc.description.versionostateczna wersja wydawcy
dc.description.volume45pl
dc.identifier.doi10.1007/s10928-018-9580-2pl
dc.identifier.eissn1573-8744pl
dc.identifier.issn1567-567Xpl
dc.identifier.projectROD UJ / OPpl
dc.identifier.urihttps://ruj.uj.edu.pl/xmlui/handle/item/143119
dc.languageengpl
dc.language.containerengpl
dc.rightsUdzielam licencji. Uznanie autorstwa 4.0 Międzynarodowa*
dc.rights.licenceCC-BY
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/legalcode.pl*
dc.share.typeinne
dc.source.integratorfalse
dc.subject.entorsade de pointespl
dc.subject.endrugspl
dc.subject.entuberculosispl
dc.subject.encardiac riskpl
dc.subject.encardiac safety simulatorpl
dc.subject.ensimcyppl
dc.subject.enmodelpl
dc.subject.ensimulationpl
dc.subtypeArticlepl
dc.titleQuantitative approach for cardiac risk assessment and interpretation in tuberculosis drug developmentpl
dc.title.journalJournal of Pharmacokinetics and Pharmacodynamicspl
dc.typeJournalArticlepl
dspace.entity.typePublication
dc.abstract.enpl
Cardiotoxicity is among the top drug safety concerns, and is of specific interest in tuberculosis, where this is a known or potential adverse event of current and emerging treatment regimens. As there is a need for a tool, beyond the QT interval, to quantify cardiotoxicity early in drug development, an empirical decision tree based classifier was developed to predict the risk of Torsades de pointes (TdP). The cardiac risk algorithm was developed using pseudo-electrocardiogram (ECG) outputs derived from cardiac myocyte electromechanical model simulations of increasing concentrations of 96 reference compounds which represented a range of clinical TdP risk. The algorithm correctly classified 89% of reference compounds with moderate sensitivity and high specificity (71 and 96%, respectively) as well as 10 out of 12 external validation compounds and the anti-TB drugs moxifloxacin and bedaquiline. The cardiac risk algorithm is suitable to help inform early drug development decisions in TB and will evolve with the addition of emerging data.
dc.affiliationpl
Wydział Farmaceutyczny : Zakład Farmacji Społecznej
dc.cm.date
2020-01-07
dc.cm.id
88552
dc.contributor.authorpl
Polak, Sebastian - 133197
dc.contributor.authorpl
Romero, Klaus
dc.contributor.authorpl
Berg, Alexander
dc.contributor.authorpl
Patel, Nikunjkumar
dc.contributor.authorpl
Jamei, Masoud
dc.contributor.authorpl
Hermann, David
dc.contributor.authorpl
Hanna, Debra
dc.date.accessioned
2020-01-17T09:58:42Z
dc.date.available
2020-01-17T09:58:42Z
dc.date.issuedpl
2018
dc.date.openaccess
0
dc.description.accesstime
w momencie opublikowania
dc.description.numberpl
3
dc.description.physicalpl
457-467
dc.description.pointspl
25
dc.description.version
ostateczna wersja wydawcy
dc.description.volumepl
45
dc.identifier.doipl
10.1007/s10928-018-9580-2
dc.identifier.eissnpl
1573-8744
dc.identifier.issnpl
1567-567X
dc.identifier.projectpl
ROD UJ / OP
dc.identifier.uri
https://ruj.uj.edu.pl/xmlui/handle/item/143119
dc.languagepl
eng
dc.language.containerpl
eng
dc.rights*
Udzielam licencji. Uznanie autorstwa 4.0 Międzynarodowa
dc.rights.licence
CC-BY
dc.rights.uri*
http://creativecommons.org/licenses/by/4.0/legalcode.pl
dc.share.type
inne
dc.source.integrator
false
dc.subject.enpl
torsade de pointes
dc.subject.enpl
drugs
dc.subject.enpl
tuberculosis
dc.subject.enpl
cardiac risk
dc.subject.enpl
cardiac safety simulator
dc.subject.enpl
simcyp
dc.subject.enpl
model
dc.subject.enpl
simulation
dc.subtypepl
Article
dc.titlepl
Quantitative approach for cardiac risk assessment and interpretation in tuberculosis drug development
dc.title.journalpl
Journal of Pharmacokinetics and Pharmacodynamics
dc.typepl
JournalArticle
dspace.entity.type
Publication
Affiliations

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