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PK/PD modelling of the QT interval : a step towards defining the translational relationship between in vitro, awake Beagle dogs, and humans

(2016) AAPS JOURNAL. 18(4). p.1000-1012
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Abstract
Inhibiting the human ether-a-go-go-related gene (hERG)-encoded potassium ion channel is positively correlated with QT-interval prolongation in vivo, which is considered a risk factor for the occurrence of Torsades de Pointes (TdP). A pharmacokinetic/pharmacodynamic model was developed for four compounds that reached the clinic, to relate drug-induced QT-interval change in awake dogs and humans and to derive a translational scaling factor a (1). Overall, dogs were more sensitive than humans to QT-interval change, an a (1) of 1.5 was found, and a 10% current inhibition in vitro produced a higher percent QT-interval change in dogs as compared to humans. The QT-interval changes in dogs were predictive for humans. In vitro and in vivo information could reliably describe the effects in humans. Robust translational knowledge is likely to reduce the need for expensive thorough QT studies; therefore, expanding this work to more compounds is recommended.
Keywords
PROARRHYTHMIC RISK, SAFETY ASSESSMENT, CLINICAL-PHASE, THOROUGH QT, PROLONGATION, PREDICTION, LIABILITY, INDUSTRY, in vitro awake beagle dogs and humans, in vitro current inhibition, percent critical threshold, QT-interval change, translational scaling, factor

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Citation

Please use this url to cite or link to this publication:

Chicago
Marostica, Eleonora, Karel Van Ammel, Ard Teisman, David Gallacher, Jan Van Bocxlaer, Filip De Ridder, Koen Boussery, and An Vermeulen. 2016. “PK/PD Modelling of the QT Interval : a Step Towards Defining the Translational Relationship Between in Vitro, Awake Beagle Dogs, and Humans.” Aaps Journal 18 (4): 1000–1012.
APA
Marostica, E., Van Ammel, K., Teisman, A., Gallacher, D., Van Bocxlaer, J., De Ridder, F., Boussery, K., et al. (2016). PK/PD modelling of the QT interval : a step towards defining the translational relationship between in vitro, awake Beagle dogs, and humans. AAPS JOURNAL, 18(4), 1000–1012.
Vancouver
1.
Marostica E, Van Ammel K, Teisman A, Gallacher D, Van Bocxlaer J, De Ridder F, et al. PK/PD modelling of the QT interval : a step towards defining the translational relationship between in vitro, awake Beagle dogs, and humans. AAPS JOURNAL. 2016;18(4):1000–12.
MLA
Marostica, Eleonora, Karel Van Ammel, Ard Teisman, et al. “PK/PD Modelling of the QT Interval : a Step Towards Defining the Translational Relationship Between in Vitro, Awake Beagle Dogs, and Humans.” AAPS JOURNAL 18.4 (2016): 1000–1012. Print.
@article{8518859,
  abstract     = {Inhibiting the human ether-a-go-go-related gene (hERG)-encoded potassium ion channel is positively correlated with QT-interval prolongation in vivo, which is considered a risk factor for the occurrence of Torsades de Pointes (TdP). A pharmacokinetic/pharmacodynamic model was developed for four compounds that reached the clinic, to relate drug-induced QT-interval change in awake dogs and humans and to derive a translational scaling factor a (1). Overall, dogs were more sensitive than humans to QT-interval change, an a (1) of 1.5 was found, and a 10\% current inhibition in vitro produced a higher percent QT-interval change in dogs as compared to humans. The QT-interval changes in dogs were predictive for humans. In vitro and in vivo information could reliably describe the effects in humans. Robust translational knowledge is likely to reduce the need for expensive thorough QT studies; therefore, expanding this work to more compounds is recommended.},
  author       = {Marostica, Eleonora and Van Ammel, Karel and Teisman, Ard and Gallacher, David and Van Bocxlaer, Jan and De Ridder, Filip and Boussery, Koen and Vermeulen, An},
  issn         = {1550-7416},
  journal      = {AAPS JOURNAL},
  keyword      = {PROARRHYTHMIC RISK,SAFETY ASSESSMENT,CLINICAL-PHASE,THOROUGH QT,PROLONGATION,PREDICTION,LIABILITY,INDUSTRY,in vitro awake beagle dogs and humans,in vitro current inhibition,percent critical threshold,QT-interval change,translational scaling,factor},
  language     = {eng},
  number       = {4},
  pages        = {1000--1012},
  title        = {PK/PD modelling of the QT interval : a step towards defining the translational relationship between in vitro, awake Beagle dogs, and humans},
  url          = {http://dx.doi.org/10.1208/s12248-016-9920-3},
  volume       = {18},
  year         = {2016},
}

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