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Association Between Vomiting and QT Hysteresis: Data from a TQT Study with the Endothelin A Receptor Antagonist Clazosentan.
- Source :
-
The AAPS journal [AAPS J] 2020 Aug 03; Vol. 22 (5), pp. 103. Date of Electronic Publication: 2020 Aug 03. - Publication Year :
- 2020
-
Abstract
- This study investigated the potential QT liability of the selective endothelin-1 A receptor antagonist clazosentan at a therapeutic (20 mg/h) and supratherapeutic (60 mg/h) intravenous (i.v.) dose. A randomized, placebo- and moxifloxacin-controlled, double-blind, 3-period, crossover study was conducted in 36 healthy subjects receiving clazosentan (20 mg/h followed by 60 mg/h i.v. for 3 h each), placebo (i.v. for 6 h), and moxifloxacin (single oral dose of 400 mg concomitantly with placebo i.v. for 6 h). At least three replicate ECGs were extracted from Holter recordings at predefined time points from 1 h pre-dose to 24 h after end of infusion. Pharmacokinetic blood sampling was performed for concentration/QT analysis (primary endpoint). For moxifloxacin, the lower bound of the 90% confidence interval (CI) of baseline- and placebo-corrected QTcF (ΔΔQTcF) was > 5 ms at its maximum plasma concentration together with a positive slope of the concentration/QT regression line demonstrating assay sensitivity. For clazosentan, time of peak exposure preceded maximum ΔΔQTcF by 4 h indicating delayed QT-prolonging effects leading to invalidity of the concentration/QT analysis. The secondary by-time-point analysis revealed QT liability of clazosentan (i.e., upper bound of 90% CI ∆∆QTcF > 10 ms). Delayed QT prolongation (i.e., hysteresis) was predominantly observed in subjects with nausea and vomiting, potentially caused by vagal reaction and/or decreases in potassium concentration. By contrast, there was no association with other adverse events, food intake, or concomitant medication. In conclusion, clazosentan at therapeutic and supratherapeutic doses has QT liability with hysteresis effects being associated with nausea and vomiting.
- Subjects :
- Adult
Cross-Over Studies
Dioxanes administration & dosage
Double-Blind Method
Endothelin A Receptor Antagonists administration & dosage
Female
Humans
Male
Middle Aged
Pyridines administration & dosage
Pyrimidines administration & dosage
Sulfonamides administration & dosage
Tetrazoles administration & dosage
Young Adult
Dioxanes adverse effects
Endothelin A Receptor Antagonists adverse effects
Heart Conduction System drug effects
Long QT Syndrome chemically induced
Pyridines adverse effects
Pyrimidines adverse effects
Sulfonamides adverse effects
Tetrazoles adverse effects
Vomiting chemically induced
Subjects
Details
- Language :
- English
- ISSN :
- 1550-7416
- Volume :
- 22
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- The AAPS journal
- Publication Type :
- Academic Journal
- Accession number :
- 32748293
- Full Text :
- https://doi.org/10.1208/s12248-020-00485-6