Evaluation of Toxicity for Heart Failure Therapeutics

Link, Michael G.; Yan, Gan‐Xin; Kowey, Peter R.

doi:10.1161/circheartfailure.109.917781

Cited by 18 publications

(14 citation statements)

References 73 publications

(73 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…After BQ-123 administration, the QTc interval was prolonged to 421.3 ms compared with 394.4 ms at baseline in patients with coronary artery disease (28). A TQT study with sitaxentan showed a lack of QT prolongation (29). Therefore, the data gathered with other selective and dual (30) ERAs did not reveal clear evidence of a class-related QT liability.…”

Section: Discussionmentioning

confidence: 91%

Association Between Vomiting and QT Hysteresis: Data from a TQT Study with the Endothelin A Receptor Antagonist Clazosentan

Juif

Dingemanse

Voors-Pette

et al. 2020

AAPS J

View full text Add to dashboard Cite

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, 3period, 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 ΔΔQTcF > 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.

show abstract

Section: Discussionmentioning

confidence: 91%

Association Between Vomiting and QT Hysteresis: Data from a TQT Study with the Endothelin A Receptor Antagonist Clazosentan

Juif

Dingemanse

Voors-Pette

et al. 2020

AAPS J

View full text Add to dashboard Cite

show abstract

“…Sudden death resulting from drug-induced proarrhythmia is one of the most feared complications in pharmaceutical medicine. 1 Of particular interest in the domain of proarrhythmic cardiac safety is torsade de pointes (torsade). Torsade is a rare polymorphic ventricular arrhythmia that typically occurs in self-limiting bursts that can lead to symptoms of dizziness, palpitations, syncope, and seizures, but also an arrhythmia with potentially catastrophic consequences: drug-induced torsade can occasionally progress to ventricular fibrillation and sudden cardiac death.…”

mentioning

confidence: 99%

“…Sudden death resulting from drug‐induced proarrhythmia is one of the most feared complications in pharmaceutical medicine . Of particular interest in the domain of proarrhythmic cardiac safety is torsade de pointes (torsade).…”

mentioning

confidence: 99%

The Potential Role of the J‐T_peak Interval in Proarrhythmic Cardiac Safety: Current State of the Science From the American College of Clinical Pharmacology and the Cardiac Safety Research Consortium

Vicente

Strauss

Upreti

et al. 2019

The Journal of Clinical Pharma

View full text Add to dashboard Cite

“…As Link and colleagues observed in 2010, “One of the most feared complications in medicine is sudden death caused by drug‐induced proarrhythmia. Accordingly, concerted efforts have been made to define a drug's proarrhythmic potential before regulatory approval.” Their quote succinctly captures two aspects of proarrhythmic cardiac safety, the topic of this primer.…”

mentioning

confidence: 99%

Drug‐induced Proarrhythmia and Torsade de Pointes: A Primer for Students and Practitioners of Medicine and Pharmacy

Turner

Rodríguez

Mantovani

et al. 2018

The Journal of Clinical Pharma

Self Cite

View full text Add to dashboard Cite

Multiple marketing withdrawals due to proarrhythmic concerns occurred in the United States, Canada, and the United Kingdom in the late 1980s to early 2000s. This primer reviews the clinical implications of a drug's identified proarrhythmic liability, the issues associated with these safety-related withdrawals, and the actions taken by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and by regulatory agencies in terms of changing drug development practices and introducing new nonclinical and clinical tests to asses proarrhythmic liability. ICH Guidelines S7B and E14 were released in 2005. Since then, they have been adopted by many regional regulatory authorities and have guided nonclinical and clinical proarrhythmic cardiac safety assessments during drug development. While this regulatory paradigm has been successful in preventing drugs with unanticipated potential for inducing the rare but potentially fatal polymorphic ventricular arrhythmia torsade de pointes from entering the market, it has led to the termination of drug development programs for other potentially useful medicines because of isolated results from studies with limited predictive value. Research efforts are now exploring alternative approaches to better predict potential proarrhythmic liabilities. For example, in the domain of human electrocardiographic assessments, concentration-response modeling conducted during phase 1 clinical development has recently become an accepted alternate primary methodology to the ICH E14 "thorough QT/QTc" study for defining a drug's corrected QT interval prolongation liability under certain conditions. When a drug's therapeutic benefit is considered important at a public health level but there is also an identified proarrhythmic liability that may result from administration of the single drug in certain individuals and/or drug-drug interactions, marketing approval will be accompanied by appropriate directions in the drug's prescribing information. Health-care professionals in the fields of medicine and pharmacy need to consider the prescribing information in conjunction with individual patients' clinical characteristics and concomitant medications when prescribing and dispensing such drugs.

show abstract

Evaluation of Toxicity for Heart Failure Therapeutics

Cited by 18 publications

References 73 publications

Association Between Vomiting and QT Hysteresis: Data from a TQT Study with the Endothelin A Receptor Antagonist Clazosentan

Association Between Vomiting and QT Hysteresis: Data from a TQT Study with the Endothelin A Receptor Antagonist Clazosentan

The Potential Role of the J‐T_peak Interval in Proarrhythmic Cardiac Safety: Current State of the Science From the American College of Clinical Pharmacology and the Cardiac Safety Research Consortium

Drug‐induced Proarrhythmia and Torsade de Pointes: A Primer for Students and Practitioners of Medicine and Pharmacy

Contact Info

Product

Resources

About

Evaluation of Toxicity for Heart Failure Therapeutics

Cited by 18 publications

References 73 publications

Association Between Vomiting and QT Hysteresis: Data from a TQT Study with the Endothelin A Receptor Antagonist Clazosentan

Association Between Vomiting and QT Hysteresis: Data from a TQT Study with the Endothelin A Receptor Antagonist Clazosentan

The Potential Role of the J‐Tpeak Interval in Proarrhythmic Cardiac Safety: Current State of the Science From the American College of Clinical Pharmacology and the Cardiac Safety Research Consortium

Drug‐induced Proarrhythmia and Torsade de Pointes: A Primer for Students and Practitioners of Medicine and Pharmacy

Contact Info

Product

Resources

About

The Potential Role of the J‐T_peak Interval in Proarrhythmic Cardiac Safety: Current State of the Science From the American College of Clinical Pharmacology and the Cardiac Safety Research Consortium