title: Inter-study variability of preclinical in vivo safety studies and translational exposure-QTc relationships--a PKPD meta-analysis.
abstract: OBJECTIVE
  Preclinical cardiovascular safety studies (CVS) have been compared between facilities with respect to their sensitivity to detect drug-induced QTc prolongation (ΔQTc). Little is known about the consistency of quantitative ΔQTc predictions that are relevant for translation to humans.
  
  
  METHODS
  We derived typical ΔQTc predictions at therapeutic exposure (ΔQTcTHER ) with 95% confidence intervals (95%CI) for 3 Kv 11.1 (hERG) channel blockers (moxifloxacin, dofetilide and sotalol) from a total of 14 CVS with variable designs in the conscious dog. Population pharmacokinetic-pharmacodynamic (PKPD) analysis of each study was followed by a meta-analysis (pooling 2-6 studies including 10-32 dogs per compound) to derive meta-predictions of typical ΔQTcTHER . Meta-predictions were used as a reference to evaluate the consistency of study predictions and to relate results to those found in the clinical literature.
  
  
  RESULTS
  The 95%CIs of study-predicted ΔQTcTHER comprised in 13 out of 14 cases the meta-prediction. Overall inter-study variability (mean deviation from meta-prediction at upper level of therapeutic exposure) was 30% (range: 1-69%). Meta-ΔQTcTHER predictions for moxifloxacin, dofetilide and sotalol overlapped with reported clinical QTc prolongation when expressed as %-prolongation from baseline.
  
  
  CONCLUSIONS
  Consistent exposure-ΔQTc predictions were obtained from single preclinical dog studies of highly variable designs by systematic PKPD analysis, which is suitable for translational purposes. The good preclinical-clinical pharmacodynamic correlations obtained suggest that such an analysis should be more routinely applied to increase the informative and predictive value of results obtained from animal experiments.
authors.affiliation: Systems Pharmacology, Leiden Academic Center of Drug Research (LACDR), Leiden University, Leiden, The Netherlands.
authors.forename: V
authors.initials: V
authors.lastname: Gotta
authors.affiliation: Global Safety Pharmacology, Janssen Research & Development, Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: Cools
authors.affiliation: Global Safety Pharmacology, Janssen Research & Development, Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: van Ammel
authors.affiliation: Global Safety Pharmacology, Janssen Research & Development, Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: D J
authors.initials: DJ
authors.lastname: Gallacher
authors.affiliation: Quantitative Pharmacology and Pharmacometrics/Merck Research Laboratories, Merck & Co., Inc., Upper Gwynedd, PA, USA.
authors.forename: S A G
authors.initials: SA
authors.lastname: Visser
authors.affiliation: SALAR-Safety and Exploratory Pharmacology Department/Merck Research Laboratories, Merck & Co., Inc., Westpoint, PA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Sannajust
authors.affiliation: SALAR-Safety and Exploratory Pharmacology Department/Merck Research Laboratories, Merck & Co., Inc., Westpoint, PA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Morissette
authors.affiliation: Systems Pharmacology, Leiden Academic Center of Drug Research (LACDR), Leiden University, Leiden, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Danhof
authors.affiliation: Systems Pharmacology, Leiden Academic Center of Drug Research (LACDR), Leiden University, Leiden, The Netherlands.
authors.forename: P H
authors.initials: PH
authors.lastname: van der Graaf
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology; D053840:Brugada Syndrome; D000075224:Cardiac Conduction System Disease; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000592:standards; D005260:Female; D024841:Fluoroquinolones / Q000009:adverse effects / Q000494:pharmacology; D006329:Heart Conduction System / Q000002:abnormalities / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D000077266:Moxifloxacin; D010627:Phenethylamines / Q000009:adverse effects / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000009:adverse effects* / Q000494:pharmacology; D015203:Reproducibility of Results; D013015:Sotalol / Q000009:adverse effects / Q000494:pharmacology; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology; D013686:Telemetry / Q000379:methods / Q000592:standards*; D057170:Translational Research, Biomedical / Q000379:methods / Q000592:standards*
chemical_list: D024841:Fluoroquinolones; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; D013015:Sotalol; C063533:dofetilide; D000077266:Moxifloxacin