title: Model-based evaluation of drug-induced QTc prolongation for compounds in early development.
abstract: OBJECTIVE
  Significant differences between dogs and humans have been observed in the concentration-QTc effect relationship of compounds with known pro-arrhythmic properties. These findings suggest that interspecies differences must be considered when evaluating drug effects. The aim of this study was to evaluate the performance of a model-based approach to assess the risk of QTc prolongation for three investigational compounds (NCE01, NCE02 and NCE03).
  
  
  METHODS
  Pharmacokinetic and pharmacodynamic data from experiments in conscious dogs and healthy subjects were included in this analysis. Pharmacokinetic modelling and deconvolution methods were applied to derive drug concentrations at the time of each QT measurement. An integrated pharmacokinetic-pharmacodynamic (PKPD) model was then used to describe QT prolongation. A threshold of ≥10 ms was used to characterize the probability of QTc prolongation.
  
  
  RESULTS
  The PKPD relationships of all three compounds were successfully described in both species. A strong effect was observed after administration of NCE01 to dogs and humans, with a slope of 0.0061 and 0.0662 ms nm(-1), respectively, and maximal probability of QTc prolongation ≥10 ms at peak concentration. For NCE02 and NCE03, QTc-shortening and borderline QT effects were observed both in dogs and humans, as described by negative or very shallow slopes (NCE02, -0.00098 and -0.01 ms nm(-1); NCE03, 0.00064 and -0.0002 ms nm(-1)).
  
  
  CONCLUSIONS
  Whilst NEC01 shows clear pro-arrhythmic effects, the liability for QT/QTc prolongation for NCE02 and NCE03 can be deemed low at the expected therapeutic exposure. Moreover, our results show the advantages of an integrated PKPD approach as the basis for translating pro-arrhythmic effects from dogs to humans.
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Vincent F S
authors.initials: VF
authors.lastname: Dubois
authors.forename: Huixin
authors.initials: H
authors.lastname: Yu
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.forename: Oscar
authors.initials: O
authors.lastname: Della Pasqua
mesh_terms: D000328:Adult; D000818:Animals; D004285:Dogs; D004311:Double-Blind Method; D055808:Drug Discovery; D015507:Drugs, Investigational / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000175:diagnosis*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D057170:Translational Research, Biomedical; D055815:Young Adult
chemical_list: D015507:Drugs, Investigational
keywords: Bayesian modelling; QT interval prolongation; cardiovascular safety; drug development; pharmacokinetic-pharmacodynamic modelling; translational pharmacology
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