title: Sensitivity of pharmacokinetic-pharmacodynamic analysis for detecting small magnitudes of QTc prolongation in preclinical safety testing.
abstract: BACKGROUND
  Preclinical concentration-effect (pharmacokinetic-pharmacodynamic, PKPD) modeling has successfully quantified QT effects of several drugs known for significant QT prolongation. This study investigated its sensitivity for detecting small magnitudes of QT-prolongation in a typical preclinical cardiovascular (CV) safety study in the conscious telemetered dog (crossover study in 4-8 animals receiving a vehicle and three dose levels). Results were compared with conventional statistical analysis (analysis of covariance, ANCOVA).
  
  
  METHODS
  A PKPD model predicting individual QTc was first developed from vehicle arms of 28 typical CV studies and one positive control study (sotalol). The model quantified between-animal, inter-occasion and within-animal variability and described QTc over 24h as a function of circadian variation and drug concentration. This "true" model was used to repeatedly (n = 500) simulate studies with typical drug-induced QTc prolongation (∆QTc) of 1 to 12 ms at high-dose peak concentrations. Simulated studies were re-analyzed by both PKPD analysis (with varying complexity) and ANCOVA. Sensitivity (power) was calculated as the percentage of studies in which a significant (α = 0.05) drug effect was found. One simulation scenario did not include a concentration-effect relationship and served to investigate false-positive rates. Exposure-effect relationships were derived from both PKPD analysis (linear concentration-effect) and ANCOVA (linear trend test for dose) and compared.
  
  
  RESULTS
  PKPD analysis/ANCOVA had a sensitivity of 80% to detect the effects of 7/13 ms (n = 4), 5/10 ms (n = 6) and 4.5/8 ms (n = 8), respectively. The false-positive rate was much higher using ANCOVA (40%) compared to PKPD analysis (1%). Typical drug effects were more precisely predicted using estimated concentration-effect slopes (± 1.5-2.8 ms) than dose-effect slopes (± 3.3-3.7 ms).
  
  
  CONCLUSIONS
  Preclinical PKPD analysis can increase the confidence in the quantification of small QTc effects and potentially allow reducing the number of animals while maintaining the required study sensitivity. This underscores the value of PKPD modeling in preclinical safety testing.
authors.affiliation: Systems Pharmacology, Leiden Academic Center of Drug Research (LACDR), Leiden University, Leiden, The Netherlands. Electronic address: v.gotta@lacdr.leidenuniv.nl.
authors.forename: Verena
authors.initials: V
authors.lastname: Gotta
authors.affiliation: Global Safety Pharmacology, Janssen Research & Development, Janssen Pharmaceutica NV, Beerse, Belgium. Electronic address: fcools@its.jnj.com.
authors.forename: Frank
authors.initials: F
authors.lastname: Cools
authors.affiliation: Global Safety Pharmacology, Janssen Research & Development, Janssen Pharmaceutica NV, Beerse, Belgium. Electronic address: kvammel@its.jnj.com.
authors.forename: Karel
authors.initials: K
authors.lastname: van Ammel
authors.affiliation: Global Safety Pharmacology, Janssen Research & Development, Janssen Pharmaceutica NV, Beerse, Belgium. Electronic address: dgallach@its.jnj.com.
authors.forename: David J
authors.initials: DJ
authors.lastname: Gallacher
authors.affiliation: Quantitative Pharmacology and Pharmacometrics, Merck Research Laboratories, Merck & Co., Inc., Upper Gwynedd, PA, USA. Electronic address: sandra.visser@merck.com.
authors.forename: Sandra A G
authors.initials: SA
authors.lastname: Visser
authors.affiliation: SALAR, Safety and Exploratory Pharmacology Department, Merck Research Laboratories, Merck & Co., Inc., West Point, PA, USA. Electronic address: frederick.sannajust@merck.com.
authors.forename: Frederick
authors.initials: F
authors.lastname: Sannajust
authors.affiliation: SALAR, Safety and Exploratory Pharmacology Department, Merck Research Laboratories, Merck & Co., Inc., West Point, PA, USA. Electronic address: pierre_morissette@merck.com.
authors.forename: Pierre
authors.initials: P
authors.lastname: Morissette
authors.affiliation: Systems Pharmacology, Leiden Academic Center of Drug Research (LACDR), Leiden University, Leiden, The Netherlands. Electronic address: m.danhof@lacdr.leidenuniv.nl.
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.affiliation: Systems Pharmacology, Leiden Academic Center of Drug Research (LACDR), Leiden University, Leiden, The Netherlands. Electronic address: p.vandergraaf@lacdr.leidenuniv.nl.
authors.forename: Piet H
authors.initials: PH
authors.lastname: van der Graaf
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000175:diagnosis; D003198:Computer Simulation; D018592:Cross-Over Studies; D004283:Dog Diseases / Q000139:chemically induced*; D004285:Dogs; D008954:Models, Biological; D012680:Sensitivity and Specificity; D013015:Sotalol / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D013015:Sotalol
keywords: Drug response; Drug safety biomarkers; Methods; Mixed-effect modeling; Statistical methods; Toxicology