title: Pharmacokinetic-pharmacodynamic modelling of drug-induced QTc interval prolongation in man: prediction from in vitro human ether-à-go-go-related gene binding and functional inhibition assays and conscious dog studies.
abstract: Functional measures of human ether-à-go-go-related gene (hERG; Kv 11.1) channel inhibition have been prioritized as an in vitro screening tool for candidate molecules. However, it is unclear how these results can be translated to humans. Here, we explore how data on drug binding and functional inhibition in vitro relate to QT prolongation in vivo. Using cisapride, sotalol and moxifloxacin as paradigm compounds, we assessed the relationship between drug concentrations, binding, functional measures and in vivo effects in preclinical species and humans.
  
  
  
  Pharmacokinetic-pharmacodynamic modelling was used to characterize the drug effects in hERG functional patch clamp, hERG radio-labelled dofetilide displacement experiments and QT interval in conscious dogs. Data were analysed in parallel to identify potential correlations between pharmacological activity in vitro and in vivo.
  
  
  
  An Emax model could not be used due to large variability in the functional patch clamp assay. Dofetilide displacement revealed that binding curves are unrelated to the in vivo potency estimates for QTc prolongation in dogs and humans. Mean in vitro potency estimates ranged from 99.9 nM for cisapride to 1030 μM for moxifloxacin.
  
  
  
  The lack of standardized protocols for in vitro assays leads to significant differences in experimental conditions, making the assessment of in vitro-in vivo correlations unreliable. Identification of an accurate safety window during the screening of candidate molecules requires a quantitative framework that disentangles system- from drug-specific properties under physiological conditions, enabling translation of the results to humans. Similar considerations will be relevant for the comprehensive in vitro pro-arrhythmia assay initiative.
authors.affiliation: Leiden Academic Centre for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands.
authors.forename: V F S
authors.initials: VF
authors.lastname: Dubois
authors.affiliation: Leiden Academic Centre for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Casarotto
authors.affiliation: Leiden Academic Centre for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Danhof
authors.affiliation: Leiden Academic Centre for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands. o.dellapasqua@ucl.ac.uk.|Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Uxbridge, UK. o.dellapasqua@ucl.ac.uk.|Clinical Pharmacology and Therapeutics, School of Life and Medical Sciences, University College London, London, UK. o.dellapasqua@ucl.ac.uk.
authors.forename: O
authors.initials: O
authors.lastname: Della Pasqua
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002478:Cells, Cultured; D020117:Cisapride / Q000493:pharmacokinetics*; D003243:Consciousness; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D024841:Fluoroquinolones / Q000493:pharmacokinetics*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D023421:Models, Animal; D008954:Models, Biological; D000077266:Moxifloxacin; D010627:Phenethylamines / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000493:pharmacokinetics*
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D024841:Fluoroquinolones; D010627:Phenethylamines; D013449:Sulfonamides; C063533:dofetilide; D000077266:Moxifloxacin; D020117:Cisapride