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.
J Clin Pharmacol
; 55(10): 1137-46, 2015 Oct.
Article
en En
| MEDLINE
| ID: mdl-25904041
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.
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Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Piridazinas
/
Isoquinolinas
Tipo de estudio:
Clinical_trials
Límite:
Adolescent
/
Adult
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Female
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Humans
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Male
/
Middle aged
Idioma:
En
Revista:
J Clin Pharmacol
Año:
2015
Tipo del documento:
Article
País de afiliación:
Estados Unidos