title: Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities.
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.
authors.affiliation: Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ghent, Belgium. eleonora.marostica@unipv.it.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Marostica
authors.affiliation: Global Safety Pharmacology, Janssen R&D, Beerse, Belgium.
authors.forename: Karel
authors.initials: K
authors.lastname: Van Ammel
authors.affiliation: Global Safety Pharmacology, Janssen R&D, Beerse, Belgium.
authors.forename: Ard
authors.initials: A
authors.lastname: Teisman
authors.affiliation: Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ghent, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Boussery
authors.affiliation: Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ghent, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Van Bocxlaer
authors.affiliation: Model Based Drug Development, Janssen R&D, Beerse, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: De Ridder
authors.affiliation: Global Safety Pharmacology, Janssen R&D, Beerse, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Gallacher
authors.affiliation: Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ghent, Belgium.|Model Based Drug Development, Janssen R&D, Beerse, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Vermeulen
mesh_terms: D000200:Action Potentials; D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D001499:Bayes Theorem; D004285:Dogs; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D024841:Fluoroquinolones / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D057809:HEK293 Cells; D006329:Heart Conduction System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D023421:Models, Animal; D008955:Models, Cardiovascular; D015233:Models, Statistical; D000077266:Moxifloxacin; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000633:toxicity; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D013045:Species Specificity; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D018675:Toxicity Tests; D014162:Transfection; D057170:Translational Research, Biomedical
chemical_list: D000900:Anti-Bacterial Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D024841:Fluoroquinolones; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D000077266:Moxifloxacin
keywords: In vitro, awake dogs and humans; NONMEM and WinBUGS; Probability; QT-interval prolongation; Translational approach