ReviewToxicological sciences : an official journal of the Society of Toxicology2022
The Challenges of Predicting Drug-Induced QTc Prolongation in Humans.
Review in Toxicological sciences : an official journal of the Society of Toxicology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
17 citing papers in PubMed, 1 synthesis or guideline pooled it, 43 citations in OpenAlex.
- QT Prolongation Risk of Antibody-Drug Conjugates.Drug safety · 2026Pooled it
- Effect of a Supratherapeutic Dose of Omaveloxolone on the Corrected QT Interval in Healthy Participants: A Randomized, Double-Blind, Placebo- and Active-Controlled, Three-Way Crossover Study.Clinical and translational science · 2025Trial
- Concentration-QTc and cardiac safety analysis of single and multiple zavegepant nasal spray doses in healthy participants to support approval.CPT: pharmacometrics & systems pharmacology · 2024Trial
- No clinically relevant electrocardiogram effects in a randomized TQT study of single therapeutic/supratherapeutic rimegepant doses in healthy adults.Clinical and translational science · 2024Trial
- A randomized, double-blind, crossover study of the effect of the fluoroquinolone moxifloxacin on glucose levels and insulin sensitivity in young men and women.Diabetes, obesity & metabolism · 2023Trial
- The Hidden Cost of QTc Assessment: A Quantitative Weight of Evidence Framework to Eliminate Structural False Positives and Restore the Lost Opportunity Cost of Abandoned Medicines.Clinical pharmacology and therapeutics · 2026Review
- In silico modeling of methadone-related ion current effects to predict QT interval prolongation.Journal of pharmacokinetics and pharmacodynamics · 2026Article
- A comprehensive review of 20 years of progress in nonclinical QT evaluation and proarrhythmic assessment.Journal of pharmacokinetics and pharmacodynamics · 2025Review
- Modelling of clinical TQT studies outcomes from preclinical cardiovascular safety pharmacology studies using the one-step QTc model.Frontiers in pharmacology · 2025Article
- Cardiovascular safety pharmacology: beyond arrhythmic risk assessment.Frontiers in cardiovascular medicine · 2025Review
- Fast and accurate prediction of drug induced proarrhythmic risk with sex specific cardiac emulators.NPJ digital medicine · 2024Article
- Use of optical techniques to evaluate the ionizing radiation effects on biological specimens.Journal of radiation research · 2024Review
- Impact of an inpatient pharmacist-driven renal dosing policy on order verification time and patient safety.SAGE open medicine · 2024Article
- Testing the nonclinical Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm with an established anti-seizure medication: Levetiracetam case study.Pharmacology research & perspectives · 2023Article
- Predicting human cardiac QT alterations and pro-arrhythmic effects of compounds with a 3D beating heart-on-chip platform.Toxicological sciences : an official journal of the Society of Toxicology · 2023Article
- Validation of a Clinical Decision Support Tool for Quantifying Risk of Torsades de Pointes in a Psychiatric Inpatient Population.Innovations in clinical neuroscienceArticle
- Collaborative science in action: A 20 year perspective from the Health and Environmental Sciences Institute (HESI) Cardiac Safety Committee.Journal of pharmacological and toxicological methodsReview
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors at 8 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The content of this article derives from a Health and Environmental Sciences Institute (HESI) consortium with a focus to improve cardiac safety during drug development. A detailed literature review was conducted to evaluate the concordance between nonclinical repolarization assays and the clinical thorough QT (TQT) study. Food and Drug Administration and HESI developed a joint database of nonclinical and clinical data, and a retrospective analysis of 150 anonymized drug candidates was reviewed to compare the performance of 3 standard nonclinical assays with clinical TQT study findings as well as investigate mechanism(s) potentially responsible for apparent discrepancies identified. The nonclinical assays were functional (IKr) current block (Human ether-a-go-go related gene), action potential duration, and corrected QT interval in animals (in vivo corrected QT). Although these nonclinical assays demonstrated good specificity for predicting negative clinical QT prolongation, they had relatively poor sensitivity for predicting positive clinical QT prolongation. After review, 28 discordant TQT-positive drugs were identified. This article provides an overview of direct and indirect mechanisms responsible for QT prolongation and theoretical reasons for lack of concordance between clinical TQT studies and nonclinical assays. We examine 6 specific and discordant TQT-positive drugs as case examples. These were derived from the unique HESI/Food and Drug Administration database. We would like to emphasize some reasons for discordant data including, insufficient or inadequate nonclinical data, effects of the drug on other cardiac ion channels, and indirect and/or nonelectrophysiological effects of drugs, including altered heart rate. We also outline best practices that were developed based upon our evaluation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.