caa a22 4500 605533830 CHVBK 20210128100840.0 cr unu---uuuuu 210128e20151201xx s 000 0 eng 10.1007/s10928-015-9434-0 doi (NATIONALLICENCE)springer-10.1007/s10928-015-9434-0 Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities [Elektronische Daten] [Eleonora Marostica, Karel Van Ammel, Ard Teisman, Koen Boussery, Jan Van Bocxlaer, Filip De Ridder, David Gallacher, An Vermeulen] 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. Springer Science+Business Media New York, 2015 QT-interval prolongation nationallicence In vitro, awake dogs and humans nationallicence NONMEM and WinBUGS nationallicence Translational approach nationallicence Probability nationallicence Marostica Eleonora Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ghent, Belgium aut Van Ammel Karel Global Safety Pharmacology, Janssen R&D, Beerse, Belgium aut Teisman Ard Global Safety Pharmacology, Janssen R&D, Beerse, Belgium aut Boussery Koen Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ghent, Belgium aut Van Bocxlaer Jan Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ghent, Belgium aut De Ridder Filip Model Based Drug Development, Janssen R&D, Beerse, Belgium aut Gallacher David Global Safety Pharmacology, Janssen R&D, Beerse, Belgium aut Vermeulen An Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ghent, Belgium aut Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/6(2015-12-01), 659-679 1567-567X 42:6<659 2015 42 10928 https://doi.org/10.1007/s10928-015-9434-0 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10928-015-9434-0 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Marostica Eleonora Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ghent, Belgium aut NATIONALLICENCE 700 1- Van Ammel Karel Global Safety Pharmacology, Janssen R&D, Beerse, Belgium aut NATIONALLICENCE 700 1- Teisman Ard Global Safety Pharmacology, Janssen R&D, Beerse, Belgium aut NATIONALLICENCE 700 1- Boussery Koen Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ghent, Belgium aut NATIONALLICENCE 700 1- Van Bocxlaer Jan Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ghent, Belgium aut NATIONALLICENCE 700 1- De Ridder Filip Model Based Drug Development, Janssen R&D, Beerse, Belgium aut NATIONALLICENCE 700 1- Gallacher David Global Safety Pharmacology, Janssen R&D, Beerse, Belgium aut NATIONALLICENCE 700 1- Vermeulen An Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ghent, Belgium aut NATIONALLICENCE 773 0- Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/6(2015-12-01), 659-679 1567-567X 42:6<659 2015 42 10928