ArticleBritish journal of clinical pharmacology2013
Not-in-trial simulation I: Bridging cardiovascular risk from clinical trials to real-life conditions.
Article 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 15 papers.
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Who cites it
15 citing papers in PubMed.
- An open-label, single-arm, dose-escalating concentration-QT study to investigate the cardiac effects and safety of paroxetine in healthy adults.British journal of clinical pharmacology · 2026Article
- Critical Roles for Modeling and Simulation and Real-World Evidence to Inform Challenges in Clinical Trial Diversity Planning.Clinical and translational science · 2025Review
- Baseline Characteristics and Maintenance Therapy Choice on Symptom Control, Reliever Use, Exacerbation Risk in Moderate-Severe Asthma: A Clinical Modelling and Simulation Study.Advances in therapy · 2024Article
- A Simulation Study of the Effect of Clinical Characteristics and Treatment Choice on Reliever Medication Use, Symptom Control and Exacerbation Risk in Moderate-Severe Asthma.Advances in therapy · 2024Article
- Understanding the Clinical Implications of Individual Patient Characteristics and Treatment Choice on the Risk of Exacerbation in Asthma Patients with Moderate-Severe Symptoms.Advances in therapy · 2023Article
- Pharmacokinetic interactions and dosing rationale for antiepileptic drugs in adults and children.British journal of clinical pharmacology · 2018Article
- Computational Modeling of Electrophysiology and Pharmacotherapy of Atrial Fibrillation: Recent Advances and Future Challenges.Frontiers in physiology · 2018Review
- Characterizing QT interval prolongation in early clinical development: a case study with methadone.Pharmacology research & perspectives · 2017Article
- 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
- Levofloxacin-Induced QTc Prolongation Depends on the Time of Drug Administration.CPT: pharmacometrics & systems pharmacology · 2016Article
- Integration of PKPD relationships into benefit-risk analysis.British journal of clinical pharmacology · 2015Review
- Generating Virtual Patients by Multivariate and Discrete Re-Sampling Techniques.Pharmaceutical research · 2015Article
- On the role of concentration-effect relationships in safety pharmacology: only the dose makes a drug not to be poison!British journal of clinical pharmacology · 2015Article
- The role of concentration-effect relationships in the assessment of QTc interval prolongation.British journal of clinical pharmacology · 2015Review
- The Rotterdam Study: 2014 objectives and design update.European journal of epidemiology · 2013Article
Corrections and comments
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Authors and funding
8 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimsThe assessment of heart rate-corrected QT (QTc) interval prolongation relies on the evidence of drug effects in healthy subjects. This study demonstrates the relevance of pharmacokinetic-pharmacodynamic (PKPD) relationships to characterize drug-induced QTc interval prolongation and explore the discrepancies between clinical trials and real-life conditions.
methodsd,l-Sotalol data from healthy subjects and from the Rotterdam Study cohort were used to assess treatment response in a phase I setting and in a real-life conditions, respectively. Using modelling and simulation, drug effects at therapeutic doses were predicted in both populations.
resultsInclusion criteria were shown to restrict the representativeness of the trial population in comparison to real-life conditions. A significant part of the typical patient population was excluded from trials due to weight and baseline QTc interval criteria. Relative risk was significantly different between sotalol users with and without heart failure, hypertension, diabetes and myocardial infarction (P < 0.01). Although drug effects do cause an increase in the relative risk of QTc interval prolongation, the presence of diabetes represented an increase from 4.0 [95% confidence interval (CI) 2.7-5.8] to 6.5 (95% CI 1.6-27.1), whilst for myocardial infarction it increased from 3.4 (95% CI 2.3-5.13) to 15.5 (95% CI 4.9-49.3).
conclusionsOur findings show that drug effects on QTc interval do not explain the observed QTc values in the population. The prevalence of high QTc values in the real-life population can be assigned to co-morbidities and concomitant medications. These findings substantiate the need to account for these factors when evaluating the cardiovascular risk of medicinal products.
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