title: Preclinical QT safety assessment: cross-species comparisons and human translation from an industry consortium.
abstract: BACKGROUND
  In vivo models have been required to demonstrate relative cardiac safety, but model sensitivity has not been systematically investigated. Cross-species and human translation of repolarization delay, assessed as QT/QTc prolongation, has not been compared employing common methodologies across multiple species and sites. Therefore, the accurate translation of repolarization results within and between preclinical species, and to man, remains problematic.
  
  
  METHODS
  Six pharmaceutical companies entered into an informal consortium designed to collect high-resolution telemetered data in multiple species (dog; n=34, cynomolgus; n=37, minipig; n=12, marmoset; n=14, guinea pig; n=5, and man; n=57). All animals received vehicle and varying doses of moxifloxacin (3-100 mg/kg, p.o.) with telemetered ECGs (≥500 Hz) obtained for 20-24h post-dose. Individual probabilistic QT-RR relationships were derived for each subject. The rate-correction efficacies of the individual (QTca) and generic correction formulae (Bazett, Fridericia, and Van de Water) were objectively assessed as the mean squared slopes of the QTc-RR relationships. Normalized moxifloxacin QTca responses (Veh Δ%/μM) were derived for 1h centered on the moxifloxacin Tmax.
  
  
  RESULTS
  All QT-RR ranges demonstrated probabilistic uncertainty; slopes varied distinctly by species where dog and human exhibited the lowest QT rate-dependence, which was much steeper in the cynomolgus and guinea pig. Incorporating probabilistic uncertainty, the normalized QTca-moxifloxacin responses were similarly conserved across all species, including man.
  
  
  CONCLUSIONS
  The current results provide the first unambiguous evidence that all preclinical in vivo repolarization assays, when accurately modeled and evaluated, yield results that are consistent with the conservation of moxifloxacin-induced QT prolongation across all common preclinical species. Furthermore, these outcomes are directly transferable across all species including man. The consortium results indicate that the implementation of standardized QTc data presentation, QTc reference cycle lengths, and rate-correction coefficients can markedly improve the concordance of preclinical and clinical outcomes in most preclinical species.
authors.affiliation: Charles River Laboratories, 6995 Longley Lane, Reno, NV 89511, USA. Electronic address: Henry.holzgrefe@crl.com.
authors.forename: Henry
authors.initials: H
authors.lastname: Holzgrefe
authors.affiliation: Statistik Georg Ferber GmbH, Cagliostrostrasse 14, 4125 Riehen, Switzerland. Electronic address: Statistik.Georg.Ferber@bluewin.ch.
authors.forename: Georg
authors.initials: G
authors.lastname: Ferber
authors.affiliation: Centre de Recherches Biologiques, CERB, Chemin de Montifault, 18800 Baugy, France. Electronic address: pascal.champeroux@cerb.fr.
authors.forename: Pascal
authors.initials: P
authors.lastname: Champeroux
authors.affiliation: Bristol-Myers Squibb, Discovery Toxicology, Route 206 and Provinceline Road, Princeton, NJ 08543, USA. Electronic address: Michael.gill@bms.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Gill
authors.affiliation: Chugai Pharmaceutical Co., Ltd., Research Division, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. Electronic address: hondamsk@chugai-pharm.co.jp.
authors.forename: Masaki
authors.initials: M
authors.lastname: Honda
authors.affiliation: F. Hoffmann-La Roche, Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland. Electronic address: andrea.greiter-wilke@roche.com.
authors.forename: Andrea
authors.initials: A
authors.lastname: Greiter-Wilke
authors.affiliation: MPI Research, Inc., 54943 North Main Street, Mattawan, MI 49071, USA. Electronic address: Theodore.Baird@mpiresearch.com.
authors.forename: Theodore
authors.initials: T
authors.lastname: Baird
authors.affiliation: F. Hoffmann-La Roche, Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland. Electronic address: olivier-meyer@hotmail.com.
authors.forename: Olivier
authors.initials: O
authors.lastname: Meyer
authors.affiliation: Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA. Electronic address: Muriel.saulnier@fda.hhs.gov.
authors.forename: Muriel
authors.initials: M
authors.lastname: Saulnier
mesh_terms: D000818:Animals; D002144:Callithrix; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004345:Drug Industry; D004562:Electrocardiography / Q000379:methods; D005260:Female; D024841:Fluoroquinolones / Q000009:adverse effects / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology*; D008252:Macaca fascicularis; D008297:Male; D000077266:Moxifloxacin; D013552:Swine; D013556:Swine, Miniature; D013686:Telemetry / Q000379:methods
chemical_list: D024841:Fluoroquinolones; D000077266:Moxifloxacin
keywords: Biomarker; Cynomolgus monkey; Dog; Guinea pig; Marmoset; Methods; Minipig; Moxifloxacin; Preclinical–clinical concordance; QT rate-correction