title: Pharmacokinetic-pharmacodynamic modeling of QRS-prolongation by flecainide: heart rate-dependent effects during sinus rhythm in conscious telemetered dogs.
abstract: BACKGROUND
  The duration of the QRS interval is determined by the ion currents involved in cardiac depolarization. Class I antiarrhythmic drugs reduce cardiac excitability and conduction by inhibiting Nav1.5 channels responsible for I(Na), thus increasing the QRS interval. Previous studies in humans as well as in animal models have demonstrated a more pronounced effect on QRS-prolongation during higher heart rates. In the present study, the effects of the Nav1.5 inhibitor flecainide on cardiovascular parameters, were studied in the telemetered beagle dog under normal autonomic control. The heart rate dependency of QRS prolongation was characterized using pharmacokinetic-pharmacodynamic (PKPD) modeling.
  
  
  METHODS
  Four male telemetered beagle dogs were administered placebo or flecainide (100, 150 and 200 mg) in a Latin square design. The QRS interval and heart rate were recorded, and blood samples were taken. Plasma concentrations of flecainide were fitted to a one compartment oral model and the intrapolated plasma concentrations were fitted to QRS and heart rate data sampled during 5 h after dosing.
  
  
  RESULTS
  Flecainide increased the QRS interval in all dogs, whereas there were no effects on heart rate. Using the PKPD model, a statistically significant heart rate-dependent QRS prolongation was linked to individual concentration-time profiles of flecainide.
  
  
  CONCLUSIONS
  PKPD analysis of QRS interval data from unrestrained dogs with sinus rhythm can elucidate mechanisms previously only described during controlled heart rhythm. Specific questions can therefore be addressed in generically designed cardiovascular telemetry safety studies and different types of relationships between parameters can be uncovered. In addition, the present approach can be used to better characterize drug-induced QRS effects in cardiovascular dog models.
authors.affiliation: Department of Safety Pharmacology, Safety Assessment Sweden, AstraZeneca R&D, Södertälje, Sweden; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Sällström
authors.affiliation: Department of Safety Pharmacology, Safety Assessment Sweden, AstraZeneca R&D, Södertälje, Sweden; Department of Medical Sciences, Uppsala University, Uppsala, Sweden. Electronic address: ahmad.al-saffar@medsci.uu.se.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Al-Saffar
authors.affiliation: Department of Safety Pharmacology, Safety Assessment Sweden, AstraZeneca R&D, Södertälje, Sweden; AstraZeneca Research and Development, Respiratory and Inflammatory Innovative Medicines, Department of Drug Metabolism and Pharmacokinetics, Mölndal, Sweden.
authors.forename: Rikard
authors.initials: R
authors.lastname: Pehrson
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004285:Dogs; D005424:Flecainide / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects*; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000378:metabolism; D013686:Telemetry / Q000379:methods
chemical_list: D000889:Anti-Arrhythmia Agents; D062554:NAV1.5 Voltage-Gated Sodium Channel; D005424:Flecainide
keywords: Beagle dog; Electrocardiogram; Flecainide; Flecainide acetate (PubChem CID: 41022); Modeling; Nav1.5; Pharmacokinetics; QRS