title: Prediction and modeling of effects on the QTc interval for clinical safety margin assessment, based on single-ascending-dose study data with AZD3839.
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.
authors.affiliation: 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.).
authors.forename: Erik
authors.initials: E
authors.lastname: Sparve
authors.affiliation: 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.).
authors.forename: Angelica L
authors.initials: AL
authors.lastname: Quartino
authors.affiliation: 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.).
authors.forename: Maria
authors.initials: M
authors.lastname: Lüttgen
authors.affiliation: 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.).
authors.forename: Karin
authors.initials: K
authors.lastname: Tunblad
authors.affiliation: 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.).
authors.forename: Anna Teiling
authors.initials: AT
authors.lastname: Gårdlund
authors.affiliation: 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.).
authors.forename: Johanna
authors.initials: J
authors.lastname: Fälting
authors.affiliation: 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.).
authors.forename: Robert
authors.initials: R
authors.lastname: Alexander
authors.affiliation: 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.).
authors.forename: Jens
authors.initials: J
authors.lastname: Kågström
authors.affiliation: 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.).
authors.forename: Linnea
authors.initials: L
authors.lastname: Sjödin
authors.affiliation: 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.).
authors.forename: Alexander
authors.initials: A
authors.lastname: Bulgak
authors.affiliation: 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.).
authors.forename: Ahmad
authors.initials: A
authors.lastname: Al-Saffar
authors.affiliation: 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.).
authors.forename: Matthew
authors.initials: M
authors.lastname: Bridgland-Taylor
authors.affiliation: 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.).
authors.forename: Chris
authors.initials: C
authors.lastname: Pollard
authors.affiliation: 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.
authors.forename: Michael D B
authors.initials: MD
authors.lastname: Swedberg
authors.affiliation: 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.).
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Vik
authors.affiliation: 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.).
authors.forename: Björn
authors.initials: B
authors.lastname: Paulsson
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography / Q000187:drug effects*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics; D006168:Guinea Pigs; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D008954:Models, Biological; D011743:Pyrimidines / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: C578092:AZD3839; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007211:Indoles; C000606913:KCNH2 protein, human; D011743:Pyrimidines; D053829:Amyloid Precursor Protein Secretases