title: Assessment of Interspecies Differences in Drug-Induced QTc Interval Prolongation in Cynomolgus Monkeys, Dogs and Humans.
abstract: OBJECTIVE
  The selection of the most suitable animal species and subsequent translation of the concentration-effect relationship to humans are critical steps for accurate assessment of the pro-arrhythmic risk of candidate molecules. The objective of this investigation was to assess quantitatively the differences in the QTc prolonging effects of moxifloxacin between cynomolgus monkeys, dogs and humans. The impact of interspecies differences is also illustrated for a new candidate molecule.
  
  
  METHODS
  Pharmacokinetic data and ECG recordings from pre-clinical protocols in monkeys and dogs and from a phase I trial in healthy subjects were identified for the purpose of this analysis. A previously established Bayesian model describing the combined effect of heart rate, circadian variation and drug effect on the QT interval was used to describe the pharmacokinetic-pharmacodynamic relationships. The probability of a ≥ 10 ms increase in QT was derived as measure of the pro-arrhythmic effect.
  
  
  RESULTS
  For moxifloxacin, the concentrations associated with a 50% probability of QT prolongation ≥ 10 ms (Cp50) varied from 20.3 to 6.4 and 2.6 μM in dogs, monkeys and humans, respectively. For NCE05, these values were 0.4 μM vs 2.0 μM for monkeys and humans, respectively.
  
  
  CONCLUSIONS
  Our findings reveal significant interspecies differences in the QT-prolonging effect of moxifloxacin. In addition to the dissimilarity in pharmacokinetics across species, it is likely that differences in pharmacodynamics also play an important role. It appears that, regardless of the animal model used, a translation function is needed to predict concentration-effect relationships in humans.
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: W E A
authors.initials: WE
authors.lastname: de Witte
authors.affiliation: Global DMPK, AstraZeneca R&D, Sodertalje, Sweden.
authors.forename: S A G
authors.initials: SA
authors.lastname: Visser
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. odp72514@gsk.com.|Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Stockley Park, Uxbridge, UK. odp72514@gsk.com.|Clinical Pharmacology & Therapeutics, University College London, London, UK. odp72514@gsk.com.
authors.forename: O
authors.initials: O
authors.lastname: Della Pasqua
mesh_terms: D000293:Adolescent; D000328:Adult; D000465:Algorithms; D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D017321:Clinical Trials, Phase I as Topic; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D024841:Fluoroquinolones / Q000009:adverse effects* / Q000493:pharmacokinetics; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology*; D008252:Macaca fascicularis; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D013045:Species Specificity; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D000077266:Moxifloxacin
keywords: PKPD modelling; QT interval prolongation; cardiovascular safety; drug development; interspecies differences