title: Comparison of different QT interval correction methods for heart rate and QT beat-to-beat method in a thorough QT study of triple monoamine reuptake inhibitor BMS-820836.
abstract: As BMS-820836 causes dose-dependent heart rate increases, QTcI, QTcF, QTcB, and QT beat-to-beat methods were compared in this thorough QT study in healthy subjects. Two parallel groups of subjects (n = 60 per group) received 2 mg (maximum therapeutic) or 4 mg (supratherapeutic) of BMS-820836 once daily for 14 days with uptitration. Another 60 subjects received encapsulated moxifloxacin (400 mg) or matching placebo in a nested-crossover study design. Compared with QTcF and QTcB, baseline QTcI had the smallest and near-zero Pearson correlation coefficient with heart rate (0.0938), which supported the choice of QTcI as the primary electrocardiographic end point. BMS-820836 was not associated with prolongation of the QT interval at the doses tested; however, ΔΔQTbtb showed the smallest deviation from 0 milliseconds compared with ΔΔQTcI and ΔΔQTcF. The ΔΔQTbtb results appeared to be more consistent with the very low likelihood of any effect on the QT interval by BMS-820836 based on the wide margin (>400×) of the in vitro hERG IC50 and free plasma concentration. Further, this is the first published study that used the nested-crossover design and QTbtb analysis in a thorough QT study. Assay sensitivity was confirmed with encapsulated moxifloxacin.
authors.affiliation: Exploratory Clinical and Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Global Biometric Sciences, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: David
authors.initials: D
authors.lastname: Burt
authors.affiliation: Exploratory Clinical and Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Wai
authors.initials: W
authors.lastname: Chan
authors.affiliation: Bioanalytical Sciences, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Dara
authors.initials: D
authors.lastname: Hawthorne
authors.affiliation: Exploratory Clinical and Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Maciej
authors.initials: M
authors.lastname: Gasior
authors.affiliation: Exploratory Clinical and Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Zubin
authors.initials: Z
authors.lastname: Bhagwagar
authors.affiliation: Exploratory Clinical and Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Keswani
authors.affiliation: Exploratory Clinical and Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Malaz
authors.initials: M
authors.lastname: AbuTarif
authors.affiliation: Exploratory Clinical and Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Bertz
mesh_terms: D000293:Adolescent; D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007546:Isoquinolines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D008133:Long QT Syndrome; D008297:Male; D008875:Middle Aged; D011724:Pyridazines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
chemical_list: C000594001:6-(2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3-amine; D007546:Isoquinolines; D011724:Pyridazines
keywords: BMS-820836; QT beat-to-beat; QT/QTc interval; nested-crossover; thorough QT