Evidence map›Paper›PMID 29181850›Full record

ArticleBritish journal of pharmacology2018

Can non-clinical repolarization assays predict the results of clinical thorough QT studies? Results from a research consortium.

Eunjung Park, Gary A Gintant, Daoqin Bi, Devi Kozeli, Syril D Pettit, Jennifer B Pierson, Matthew Skinner, James Willard, Todd Wisialowski, John Koerner and 1 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in British journal of pharmacology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.

0numbers the graph read from it
0cells of the map it votes in
18citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

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.

2 · The registry

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.

3 · Its place in the literature

Who cites it

18 citing papers in PubMed.

  1. Article
  2. Review
  3. Article
  4. Article
  5. Article
  6. The Challenges of Predicting Drug-Induced QTc Prolongation in Humans.Toxicological sciences : an official journal of the Society of Toxicology · 2022
    Review
  7. Review
  8. Article
  9. Review
  10. Review
  11. Review
  12. Can We Panelize Seizure?Toxicological sciences : an official journal of the Society of Toxicology · 2021
    Article
  13. Review
  14. Article
  15. QT Assessment in Early Drug Development: The Long and the Short of It.International journal of molecular sciences · 2019
    Review
  16. Article
  17. Review
  18. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors.

Eunjung ParkCenter for Drug Evaluation and Research, US FDA, Silver Spring, MD, USA.
Gary A GintantDepartment of Integrative Pharmacology, AbbVie, North Chicago, IL, USA.
Daoqin BiCenter for Drug Evaluation and Research, US FDA, Silver Spring, MD, USA.
Devi KozeliCenter for Drug Evaluation and Research, US FDA, Silver Spring, MD, USA.
Syril D PettitHESI, Washington, DC, USA.
Jennifer B PiersonHESI, Washington, DC, USA.ORCID 0000-0002-9551-0681
Matthew SkinnerDrug Safety and Metabolism, AstraZeneca, Macclesfield, Cheshire, UK.
James WillardCenter for Drug Evaluation and Research, US FDA, Silver Spring, MD, USA.
Todd WisialowskiDrug Safety Research and Development, Pfizer, Groton, CT, USA.
John KoernerCenter for Drug Evaluation and Research, US FDA, Silver Spring, MD, USA.
Jean-Pierre ValentinNon-Clinical Development, UCB-Biopharma SPRL, Braine-l'Alleud, Belgium.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

background and purposeTranslation of non-clinical markers of delayed ventricular repolarization to clinical prolongation of the QT interval corrected for heart rate (QTc) (a biomarker for torsades de pointes proarrhythmia) remains an issue in drug discovery and regulatory evaluations. We retrospectively analysed 150 drug applications in a US Food and Drug Administration database to determine the utility of established non-clinical in vitro IKr current human ether-à-go-go-related gene (hERG), action potential duration (APD) and in vivo (QTc) repolarization assays to detect and predict clinical QTc prolongation. EXPERIMENTAL APPROACH: The predictive performance of three non-clinical assays was compared with clinical thorough QT study outcomes based on free clinical plasma drug concentrations using sensitivity and specificity, receiver operating characteristic (ROC) curves, positive (PPVs) and negative predictive values (NPVs) and likelihood ratios (LRs). KEY

resultsNon-clinical assays demonstrated robust specificity (high true negative rate) but poor sensitivity (low true positive rate) for clinical QTc prolongation at low-intermediate (1×-30×) clinical exposure multiples. The QTc assay provided the most robust PPVs and NPVs (ability to predict clinical QTc prolongation). ROC curves (overall test accuracy) and LRs (ability to influence post-test probabilities) demonstrated overall marginal performance for hERG and QTc assays (best at 30× exposures), while the APD assay demonstrated minimal value. CONCLUSIONS AND IMPLICATIONS: The predictive value of hERG, APD and QTc assays varies, with drug concentrations strongly affecting translational performance. While useful in guiding preclinical candidates without clinical QT prolongation, hERG and QTc repolarization assays provide greater value compared with the APD assay.

Indexed as

Action PotentialsCardiovascular AgentsDrug Evaluation, PreclinicalDrugs, InvestigationalEther-A-Go-Go Potassium ChannelsHeart RateHumansLong QT SyndromeRetrospective StudiesTorsades de PointesCardiovascular AgentsDrugs, InvestigationalEther-A-Go-Go Potassium Channels

Identifiers

PMID29181850
PMCPMC5786459

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Registered trials

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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.