Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities
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| 024 | 7 | 0 | |a 10.1007/s10928-015-9434-0 |2 doi |
| 035 | |a (NATIONALLICENCE)springer-10.1007/s10928-015-9434-0 | ||
| 245 | 0 | 0 | |a Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities |h [Elektronische Daten] |c [Eleonora Marostica, Karel Van Ammel, Ard Teisman, Koen Boussery, Jan Van Bocxlaer, Filip De Ridder, David Gallacher, An Vermeulen] |
| 520 | 3 | |a 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. | |
| 540 | |a Springer Science+Business Media New York, 2015 | ||
| 690 | 7 | |a QT-interval prolongation |2 nationallicence | |
| 690 | 7 | |a In vitro, awake dogs and humans |2 nationallicence | |
| 690 | 7 | |a NONMEM and WinBUGS |2 nationallicence | |
| 690 | 7 | |a Translational approach |2 nationallicence | |
| 690 | 7 | |a Probability |2 nationallicence | |
| 700 | 1 | |a Marostica |D Eleonora |u Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ghent, Belgium |4 aut | |
| 700 | 1 | |a Van Ammel |D Karel |u Global Safety Pharmacology, Janssen R&D, Beerse, Belgium |4 aut | |
| 700 | 1 | |a Teisman |D Ard |u Global Safety Pharmacology, Janssen R&D, Beerse, Belgium |4 aut | |
| 700 | 1 | |a Boussery |D Koen |u Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ghent, Belgium |4 aut | |
| 700 | 1 | |a Van Bocxlaer |D Jan |u Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ghent, Belgium |4 aut | |
| 700 | 1 | |a De Ridder |D Filip |u Model Based Drug Development, Janssen R&D, Beerse, Belgium |4 aut | |
| 700 | 1 | |a Gallacher |D David |u Global Safety Pharmacology, Janssen R&D, Beerse, Belgium |4 aut | |
| 700 | 1 | |a Vermeulen |D An |u Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ghent, Belgium |4 aut | |
| 773 | 0 | |t Journal of Pharmacokinetics and Pharmacodynamics |d Springer US; http://www.springer-ny.com |g 42/6(2015-12-01), 659-679 |x 1567-567X |q 42:6<659 |1 2015 |2 42 |o 10928 | |
| 856 | 4 | 0 | |u https://doi.org/10.1007/s10928-015-9434-0 |q text/html |z Onlinezugriff via DOI |
| 898 | |a BK010053 |b XK010053 |c XK010000 | ||
| 900 | 7 | |a Metadata rights reserved |b Springer special CC-BY-NC licence |2 nationallicence | |
| 908 | |D 1 |a research-article |2 jats | ||
| 949 | |B NATIONALLICENCE |F NATIONALLICENCE |b NL-springer | ||
| 950 | |B NATIONALLICENCE |P 856 |E 40 |u https://doi.org/10.1007/s10928-015-9434-0 |q text/html |z Onlinezugriff via DOI | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Marostica |D Eleonora |u Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ghent, Belgium |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Van Ammel |D Karel |u Global Safety Pharmacology, Janssen R&D, Beerse, Belgium |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Teisman |D Ard |u Global Safety Pharmacology, Janssen R&D, Beerse, Belgium |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Boussery |D Koen |u Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ghent, Belgium |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Van Bocxlaer |D Jan |u Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ghent, Belgium |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a De Ridder |D Filip |u Model Based Drug Development, Janssen R&D, Beerse, Belgium |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Gallacher |D David |u Global Safety Pharmacology, Janssen R&D, Beerse, Belgium |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Vermeulen |D An |u Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ghent, Belgium |4 aut | ||
| 950 | |B NATIONALLICENCE |P 773 |E 0- |t Journal of Pharmacokinetics and Pharmacodynamics |d Springer US; http://www.springer-ny.com |g 42/6(2015-12-01), 659-679 |x 1567-567X |q 42:6<659 |1 2015 |2 42 |o 10928 | ||