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Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities

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Abstract
Safety pharmacology studies are performed to assess whether compounds may provoke severe arrhythmias (e.g. Torsades de Pointes, TdP) and sudden death in man. Although there is strong evidence that drugs inducing TdP in man prolong the QT interval in vivo and block the human ether-a-go-go-related gene (hERG) ion channel in vitro, not all drugs affecting the QT interval or the hERG will induce TdP. Nevertheless, QT-interval prolongation and hERG blockade currently represent the most accepted early risk biomarkers to deselect drugs. An extensive pharmacokinetic/pharmacodynamic (PK/PD) analysis is developed to understand moxifloxacin's-induced effects on the QT interval by comparing the relationship between results of an in vitro patch-clamp model to in vivo models. The frequentist and the fully Bayesian estimation procedures were compared and provided similar performances when the best model selected in NONMEM is subsequently implemented in WinBUGS, which guarantees a straightforward calculation of the probability of QT-interval prolongation greater than 2.5 % (10 ms). The use of the percent threshold to account for the intrinsic differences between species and a new calculation of the probability curve are introduced. The concentration providing the 50 % probability indicates that dogs are more sensitive than humans to QT-interval prolongation. However, based on the drug effect, a clear distinction between species cannot be made. An operational PK/PD model of agonism was used to investigate the relationship between effects on the hERG and QT-interval prolongation in dogs. The proposed analysis contributes to establish a translational relationship that could potentially reduce the need for thorough QT studies.
Keywords
NONMEM and WinBUGS, Translational approach, awake dogs and humans, In vitro, QT-interval prolongation, Probability, TORSADE-DE-POINTES, CARDIAC ELECTROPHYSIOLOGY, PROARRHYTHMIC RISK, BEAGLE DOGS, MOXIFLOXACIN, INDUSTRY, WINBUGS

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MLA
Marostica, Eleonora et al. “Modelling of Drug-induced QT-interval Prolongation: Estimation Approaches and Translational Opportunities.” JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS 42.6 (2015): 659–679. Print.
APA
Marostica, E., Van Ammel, K., Teisman, A., Boussery, K., Van Bocxlaer, J., De Ridder, F., Gallacher, D., et al. (2015). Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities. JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS, 42(6), 659–679.
Chicago author-date
Marostica, Eleonora, Karel Van Ammel, Ard Teisman, Koen Boussery, Jan Van Bocxlaer, Filip De Ridder, David Gallacher, and An Vermeulen. 2015. “Modelling of Drug-induced QT-interval Prolongation: Estimation Approaches and Translational Opportunities.” Journal of Pharmacokinetics and Pharmacodynamics 42 (6): 659–679.
Chicago author-date (all authors)
Marostica, Eleonora, Karel Van Ammel, Ard Teisman, Koen Boussery, Jan Van Bocxlaer, Filip De Ridder, David Gallacher, and An Vermeulen. 2015. “Modelling of Drug-induced QT-interval Prolongation: Estimation Approaches and Translational Opportunities.” Journal of Pharmacokinetics and Pharmacodynamics 42 (6): 659–679.
Vancouver
1.
Marostica E, Van Ammel K, Teisman A, Boussery K, Van Bocxlaer J, De Ridder F, et al. Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities. JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS. 2015;42(6):659–79.
IEEE
[1]
E. Marostica et al., “Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities,” JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS, vol. 42, no. 6, pp. 659–679, 2015.
@article{7042838,
  abstract     = {{Safety pharmacology studies are performed to assess whether compounds may provoke severe arrhythmias (e.g. Torsades de Pointes, TdP) and sudden death in man. Although there is strong evidence that drugs inducing TdP in man prolong the QT interval in vivo and block the human ether-a-go-go-related gene (hERG) ion channel in vitro, not all drugs affecting the QT interval or the hERG will induce TdP. Nevertheless, QT-interval prolongation and hERG blockade currently represent the most accepted early risk biomarkers to deselect drugs. An extensive pharmacokinetic/pharmacodynamic (PK/PD) analysis is developed to understand moxifloxacin's-induced effects on the QT interval by comparing the relationship between results of an in vitro patch-clamp model to in vivo models. The frequentist and the fully Bayesian estimation procedures were compared and provided similar performances when the best model selected in NONMEM is subsequently implemented in WinBUGS, which guarantees a straightforward calculation of the probability of QT-interval prolongation greater than 2.5 % (10 ms). The use of the percent threshold to account for the intrinsic differences between species and a new calculation of the probability curve are introduced. The concentration providing the 50 % probability indicates that dogs are more sensitive than humans to QT-interval prolongation. However, based on the drug effect, a clear distinction between species cannot be made. An operational PK/PD model of agonism was used to investigate the relationship between effects on the hERG and QT-interval prolongation in dogs. The proposed analysis contributes to establish a translational relationship that could potentially reduce the need for thorough QT studies.}},
  author       = {{Marostica, Eleonora and Van Ammel, Karel and Teisman, Ard and Boussery, Koen and Van Bocxlaer, Jan and De Ridder, Filip and Gallacher, David and Vermeulen, An}},
  issn         = {{1567-567X}},
  journal      = {{JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS}},
  keywords     = {{NONMEM and WinBUGS,Translational approach,awake dogs and humans,In vitro,QT-interval prolongation,Probability,TORSADE-DE-POINTES,CARDIAC ELECTROPHYSIOLOGY,PROARRHYTHMIC RISK,BEAGLE DOGS,MOXIFLOXACIN,INDUSTRY,WINBUGS}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{659--679}},
  title        = {{Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities}},
  url          = {{http://dx.doi.org/10.1007/s10928-015-9434-0}},
  volume       = {{42}},
  year         = {{2015}},
}

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