LBPW-1

J. Keirns,1 N. Sarapa,2 C. Benson,3 C. Dota,4 G. Ferber,5 C. Garnett,6 C. L. Green,7 V. Jarugula,8 L. Johannesen,9 K. Krudys,9 J. Liu,9 C. Ortemann-Renon,10 S. Riley,11 B. Smith,12 R. R. Stolz,13 M. Zhou,12 N. Stockbridge,9 B. Darpo14; 1Astellas Pharma Global Development, Northbrook, IL, 2Bayer Healthcare, Inc, Whippany, NJ, 3Eli Lilly & Co., Indianapolis, IN, 4AstraZeneca R&D, Mölndal, Sweden, 5Statistik.Georg.Ferber GmbH, Riehen, Switzerland, 6Certara, St. Louis, MO, 7Duke Clinical Research Institute, Durham, NC, 8Novartis Institute for Biomedical Research, East Hanover, NJ, 9US FDA, Silver Spring, MD, 10Sanofi, Bridgewater, NJ, 11Pfizer Inc., Groton, CT, 12iCardiac Technologies, Inc., Rochester, NY, 13Covance Clinical Research Unit, Evansville, IN, 14Karolinska Institutet, Stockholm, Sweden


BACKGROUND: As recommended by the ICH E14 guideline, new drugs with systemic availability typically are assessed in a so-called thorough QT study in healthy subjects. If an alternative way of QT assessment could be incorporated into a routinely performed early phase clinical pharmacology study, this would present not only a more efficient approach, but also allow improved understanding of a drug's QT liability early in clinical development.
METHODS: The QT effects of 5 'QT positive' and one negative drug were tested to evaluate whether exposure-response analysis can detect and
exclude QT effects in a small study with healthy subjects. Each drug was given to 9 subjects (6 for placebo) in two dose levels; for the positive drugs chosen to cause 10 to 12 ms and 15 to 20 ms QTcF prolongation.
RESULTS: The slope of the concentration/∆QTc effect was significantly positive for ondansetron, quinine, dolasetron, moxifloxacin and dofetilide and an effect above 10 ms could not be excluded for the lower dose,
i.e., the upper bound of the confidence interval for the predicted mean ∆∆QTcF effect was above 10 ms. For the negative drug, levocetirizine, a ∆∆QTcF effect above 10 ms was excluded at 6-fold the therapeutic dose.
CONCLUSION: The study provides evidence that robust QT assessment in early phase clinical studies can replace the thorough QT study.