2. Academic Validation
  3. Prediction and modeling of effects on the QTc interval for clinical safety margin assessment, based on single-ascending-dose study data with AZD3839

Prediction and modeling of effects on the QTc interval for clinical safety margin assessment, based on single-ascending-dose study data with AZD3839

  • J Pharmacol Exp Ther. 2014 Aug;350(2):469-78. doi: 10.1124/jpet.114.215202.
Erik Sparve 1,  Angelica L Quartino 1,  Maria Lüttgen 1,  Karin Tunblad 1,  Anna Teiling Gårdlund 1,  Johanna Fälting 1,  Robert Alexander 1,  Jens Kågström 1,  Linnea Sjödin 1,  Alexander Bulgak 1,  Ahmad Al-Saffar 1,  Matthew Bridgland-Taylor 1,  Chris Pollard 1,  Michael D B Swedberg 2,  Torbjörn Vik 1,  Björn Paulsson 1
Affiliations

Affiliations

  • 1 Karolinska Institute, Solna, Sweden (E.S.); Genentech, South San Francisco, California (A.L.Q.); Swedish Medical Product Agency, Uppsala, Sweden (M.L., A.B.); Medivir AB, Huddinge, Sweden (K.T.); Kvegerö Gård, Gnesta, Sweden (A.T.G.); Bioarctic Neuroscience, Stockholm, Sweden (J.F.); AstraZeneca Research & Development, Neuroscience iMed, Cambridge, Massachusetts (R.A.); Sörmland County Council Health Care Department, Nyköping, Sweden (J.K.); Pharmacy AB, Flora, Höganäs, Sweden (L.S.); Department of Medical Sciences, University of Uppsala, Uppsala, Sweden (A.A.-S.); Discovery Sciences, AstraZeneca, Macclesfield, Cheshire, United Kingdom (M.B.-T., C.P.); Swedberg Preclinical Partner AB (Inc.), Trosa, Sweden (M.D.B.S.); AstraZeneca Global Medicines Development, AZ ECG Centre, Mölndal, Sweden (T.V.); and Swedish Orphan Biovitrum, Stockholm, Sweden (B.P.).
  • 2 Karolinska Institute, Solna, Sweden (E.S.); Genentech, South San Francisco, California (A.L.Q.); Swedish Medical Product Agency, Uppsala, Sweden (M.L., A.B.); Medivir AB, Huddinge, Sweden (K.T.); Kvegerö Gård, Gnesta, Sweden (A.T.G.); Bioarctic Neuroscience, Stockholm, Sweden (J.F.); AstraZeneca Research & Development, Neuroscience iMed, Cambridge, Massachusetts (R.A.); Sörmland County Council Health Care Department, Nyköping, Sweden (J.K.); Pharmacy AB, Flora, Höganäs, Sweden (L.S.); Department of Medical Sciences, University of Uppsala, Uppsala, Sweden (A.A.-S.); Discovery Sciences, AstraZeneca, Macclesfield, Cheshire, United Kingdom (M.B.-T., C.P.); Swedberg Preclinical Partner AB (Inc.), Trosa, Sweden (M.D.B.S.); AstraZeneca Global Medicines Development, AZ ECG Centre, Mölndal, Sweden (T.V.); and Swedish Orphan Biovitrum, Stockholm, Sweden (B.P.) michael.swedberg@telia.com.
PMID: 24917547 DOI: 10.1124/jpet.114.215202
Abstract

Corrected QT interval (QTc) prolongation in humans is usually predictable based on results from preclinical findings. This study confirms the signal from preclinical cardiac repolarization models (human ether-a-go-go-related gene, guinea pig monophasic action potential, and dog telemetry) on the clinical effects on the QTc interval. A thorough QT/QTc study is generally required for bioavailable pharmaceutical compounds to determine whether or not a drug shows a QTc effect above a threshold of regulatory interest. However, as demonstrated in this AZD3839 [(S)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine hemifumarate] single-ascending-dose (SAD) study, high-resolution digital electrocardiogram data, in combination with adequate efficacy biomarker and pharmacokinetic data and nonlinear mixed effects modeling, can provide the basis to safely explore the margins to allow for robust modeling of clinical effect versus the electrophysiological risk marker. We also conclude that a carefully conducted SAD study may provide reliable data for effective early strategic decision making ahead of the thorough QT/QTc study.

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