title: Not-in-trial simulation I: Bridging cardiovascular risk from clinical trials to real-life conditions.
abstract: OBJECTIVE
  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.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, 2300 RA, Leiden, The Netherlands; Department of Medical Informatics, Erasmus Medical Centre, 3015 GE, Rotterdam, The Netherlands.
authors.forename: Anne S Y
authors.initials: AS
authors.lastname: Chain
authors.forename: Jeanne P
authors.initials: JP
authors.lastname: Dieleman
authors.forename: Charlotte
authors.initials: C
authors.lastname: van Noord
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Bruno H Ch
authors.initials: BH
authors.lastname: Stricker
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.forename: Miriam C J M
authors.initials: MC
authors.lastname: Sturkenboom
authors.forename: Oscar
authors.initials: O
authors.lastname: Della Pasqua
mesh_terms: D000293:Adolescent; D000319:Adrenergic beta-Antagonists / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D015331:Cohort Studies; D003198:Computer Simulation; D004562:Electrocardiography; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011446:Prospective Studies; D018570:Risk Assessment; D013015:Sotalol / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D018709:Statistics, Nonparametric; D011795:Surveys and Questionnaires; D055815:Young Adult
chemical_list: D000319:Adrenergic beta-Antagonists; D013015:Sotalol
keywords: QTc interval prolongation; model-based drug development, risk management; observational cohorts; pharmacokinetic-pharmacodynamic modelling; sotalol