Trial reportBritish journal of clinical pharmacology2013
Identifying the translational gap in the evaluation of drug-induced QTc interval prolongation.
Trial report in British journal of clinical pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers, 1 of them a synthesis that pooled it.
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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.
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Who cites it
20 citing papers in PubMed, 1 synthesis or guideline pooled it, 31 citations in OpenAlex.
- Inter-study variability of preclinical in vivo safety studies and translational exposure-QTc relationships--a PKPD meta-analysis.British journal of pharmacology · 2015Pooled it
- Predicting QRS and PR interval prolongations in humans using nonclinical data.British journal of pharmacology · 2017Trial
- Model-based evaluation of drug-induced QTc prolongation for compounds in early development.British journal of clinical pharmacology · 2015Trial
- Precision Cardio-Oncology: Use of Mechanistic Pharmacokinetic and Pharmacodynamic Modeling to Predict Cardiotoxicities of Anti-Cancer Drugs.Frontiers in oncology · 2021Review
- A tutorial on model informed approaches to cardiovascular safety with focus on cardiac repolarisation.Journal of pharmacokinetics and pharmacodynamics · 2018Article
- Can non-clinical repolarization assays predict the results of clinical thorough QT studies? Results from a research consortium.British journal of pharmacology · 2018Article
- Translating QT interval prolongation from conscious dogs to humans.British journal of clinical pharmacology · 2017Article
- Characterizing QT interval prolongation in early clinical development: a case study with methadone.Pharmacology research & perspectives · 2017Article
- Application of a systems pharmacology model for translational prediction of hERG-mediated QTc prolongation.Pharmacology research & perspectives · 2016Article
- Pharmacokinetic-pharmacodynamic modelling of drug-induced QTc interval prolongation in man: prediction from in vitro human ether-à-go-go-related gene binding and functional inhibition assays and conscious dog studies.British journal of pharmacology · 2016Article
- Evolution of strategies to improve preclinical cardiac safety testing.Nature reviews. Drug discovery · 2016Review
- PK/PD Modelling of the QT Interval: a Step Towards Defining the Translational Relationship Between In Vitro, Awake Beagle Dogs, and Humans.The AAPS journal · 2016Article
- Drug-drug interactions and QT prolongation as a commonly assessed cardiac effect - comprehensive overview of clinical trials.BMC pharmacology & toxicology · 2016Review
- Assessment of Interspecies Differences in Drug-Induced QTc Interval Prolongation in Cynomolgus Monkeys, Dogs and Humans.Pharmaceutical research · 2016Article
- Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities.Journal of pharmacokinetics and pharmacodynamics · 2015Article
- Model-based prediction of the acute and long-term safety profile of naproxen in rats.British journal of pharmacology · 2015Article
- The impact of composite AUC estimates on the prediction of systemic exposure in toxicology experiments.Journal of pharmacokinetics and pharmacodynamics · 2015Article
- Modeling and Simulation Approaches for Cardiovascular Function and Their Role in Safety Assessment.CPT: pharmacometrics & systems pharmacology · 2015Review
- The role of concentration-effect relationships in the assessment of QTc interval prolongation.British journal of clinical pharmacology · 2015Review
- Mitigating prolonged QT interval in cancer nanodrug development for accelerated clinical translation.Journal of nanobiotechnology · 2013Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimsGiven the similarities in QTc response between dogs and humans, dogs are used in pre-clinical cardiovascular safety studies. The objective of our investigation was to characterize the PKPD relationships and identify translational gaps across species following the administration of three compounds known to cause QTc interval prolongation, namely cisapride, d, l-sotalol and moxifloxacin.
methodsPharmacokinetic and pharmacodynamic data from experiments in conscious dogs and clinical trials were included in this analysis. First, pharmacokinetic modelling and deconvolution methods were applied to derive drug concentrations at the time of each QT measurement. A Bayesian PKPD model was then used to describe QT prolongation, allowing discrimination of drug-specific effects from other physiological factors known to alter QT interval duration. A threshold of ≥10 ms was used to explore the probability of prolongation after drug administration.
resultsA linear relationship was found to best describe the pro-arrhythmic effects of cisapride, d,l-sotalol and moxifloxacin both in dogs and in humans. The drug-specific parameter (slope) in dogs was statistically significantly different from humans. Despite such differences, our results show that the probability of QTc prolongation ≥10 ms in dogs nears 100% for all three compounds at the therapeutic exposure range in humans.
conclusionsOur findings indicate that the slope of PKPD relationship in conscious dogs may be used as the basis for the prediction of drug-induced QTc prolongation in humans. Furthermore, the risk of QTc prolongation can be expressed in terms of the probability associated with an increase ≥10 ms, allowing direct inferences about the clinical relevance of the pro-arrhythmic potential of a molecule.
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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.