Not-in-trial simulation I: Bridging cardiovascular risk from clinical trials to real-life conditions

Br J Clin Pharmacol. 2013 Dec;76(6):964-72. doi: 10.1111/bcp.12151.


Aims: The 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.

Methods: d,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.

Results: Inclusion 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).

Conclusions: Our 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.

Keywords: QTc interval prolongation; model-based drug development, risk management; observational cohorts; pharmacokinetic-pharmacodynamic modelling; sotalol.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adrenergic beta-Antagonists / adverse effects*
  • Adrenergic beta-Antagonists / pharmacokinetics
  • Adrenergic beta-Antagonists / pharmacology
  • Adrenergic beta-Antagonists / therapeutic use
  • Adult
  • Cohort Studies
  • Computer Simulation*
  • Electrocardiography
  • Female
  • Healthy Volunteers
  • Humans
  • Long QT Syndrome / chemically induced*
  • Long QT Syndrome / metabolism
  • Male
  • Middle Aged
  • Models, Biological*
  • Prospective Studies
  • Risk Assessment
  • Sotalol / adverse effects*
  • Sotalol / pharmacokinetics
  • Sotalol / pharmacology
  • Sotalol / therapeutic use
  • Statistics, Nonparametric
  • Surveys and Questionnaires
  • Young Adult


  • Adrenergic beta-Antagonists
  • Sotalol