Pharmacokinetic-pharmacodynamic modeling of QRS-prolongation by flecainide: Heart rate-dependent effects during sinus rhythm in conscious telemetered dogs

Journal of Pharmacological and Toxicological Methods

Volumn 69, Issue 1, 2014, Pages 24-29

  Sällström, Johan ^a,b   Al Saffar, Ahmad ^a,c   Pehrson, Rikard ^a,d  

^a ASTRAZENECA R AND D   (Sweden)

^b KAROLINSKA INSTITUTE   (Sweden)

^c UPPSALA UNIVERSITY   (Sweden)

^d ASTRAZENECA R AND D   (Sweden)

Author keywords

Beagle dog; Electrocardiogram; Flecainide; Modeling; Nav1.5; Pharmacokinetics; QRS

Indexed keywords

FLECAINIDE ACETATE; PLACEBO; SODIUM CHANNEL NAV1.5;

ANIMAL EXPERIMENT; ARTICLE; BLOOD SAMPLING; CARDIOVASCULAR PARAMETERS; COMPARTMENT MODEL; CONTROLLED STUDY; DOG; DOSE TIME EFFECT RELATION; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG EFFECT; ECG ABNORMALITY; ELECTROCARDIOGRAM; HEART RATE; HEART VENTRICLE PRESSURE; MALE; MAXIMUM PLASMA CONCENTRATION; MORNING DOSAGE; NONHUMAN; PHARMACODYNAMICS; QRS COMPLEX; QRS PROLONGATION; SINUS RHYTHM; TELEMETRY; TIME TO MAXIMUM PLASMA CONCENTRATION;

BEAGLE DOG; ELECTROCARDIOGRAM; FLECAINIDE; FLECAINIDE ACETATE (PUBCHEM CID: 41022); MODELING; NAV1.5; PHARMACOKINETICS; QRS;

ANIMALS; ANTI-ARRHYTHMIA AGENTS; DOGS; FLECAINIDE; HEART; HEART RATE; LONG QT SYNDROME; MALE; MYOCARDIUM; NAV1.5 VOLTAGE-GATED SODIUM CHANNEL; TELEMETRY;

EID: 84887000296     PISSN: 10568719     EISSN: 1873488X     Source Type: Journal    
DOI: 10.1016/j.vascn.2013.10.001     Document Type: Article

References (18)

1. Anno T., Hondeghem L.M. Interactions of flecainide with guinea pig cardiac sodium channels. Importance of activation unblocking to the voltage dependence of recovery. Circulation Research 1990, 66:789-803.
2. CAST Preliminary report: Effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. The New England Journal of Medicine 1989, 321:406-412.
3. Cavero I. Using pharmacokinetic/pharmacodynamic modelling in safety pharmacology to better define safety margins: A regional workshop of the Safety Pharmacology Society. Expert Opinion on Drug Safety 2007, 6:465-471.
4. Cros C., Skinner M., Moors J., Lainee P., Valentin J.P. Detecting drug-induced prolongation of the QRS complex: New insights for cardiac safety assessment. Toxicology and Applied Pharmacology 2012, 265:200-208.
5. Erdemli G., Kim A.M., Ju H., Springer C., Penland R.C., Hoffmann P.K. Cardiac safety implications of hNav1.5 blockade and a framework for pre-clinical evaluation. Frontiers in Pharmacology 2012, 3:6.
6. Harmer A.R., Valentin J.P., Pollard C.E. On the relationship between block of the cardiac Na(+) channel and drug-induced prolongation of the QRS complex. British Journal of Pharmacology 2011, 164:260-273.
7. Heath B.M., Cui Y., Worton S., Lawton B., Ward G., Ballini E., et al. Translation of flecainide- and mexiletine-induced cardiac sodium channel inhibition and ventricular conduction slowing from nonclinical models to clinical. Journal of Pharmacological and Toxicological Methods 2011, 63:258-268.
8. Lund L.H., Jurga J., Edner M., Benson L., Dahlstrom U., Linde C., et al. Prevalence, correlates, and prognostic significance of QRS prolongation in heart failure with reduced and preserved ejection fraction. European Heart Journal 2013, 34:529-539.
9. Malik M., Hnatkova K., Sisakova M., Schmidt G. Subject-specific heart rate dependency of electrocardiographic QT, PQ, and QRS intervals. Journal of Electrocardiology 2008, 41:491-497.
10. Ollerstam A., Persson A.H., Visser S.A., Fredriksson J.M., Forsberg T., Nilsson L.B., et al. A novel approach to data processing of the QT interval response in the conscious telemetered beagle dog. Journal of Pharmacological and Toxicological Methods 2007, 55:35-48.
11. Padrini R., Piovan D., Busa M., al-Bunni M., Maiolino P., Ferrari M. Pharmacodynamic variability of flecainide assessed by QRS changes. Clinical Pharmacology and Therapeutics 1993, 53:59-64.
12. Ramos E., O'Leary M.E. State-dependent trapping of flecainide in the cardiac sodium channel. The Journal of Physiology 2004, 560:37-49.
13. Salerno D.M., Granrud G., Sharkey P., Krejci J., Larson T., Erlien D., et al. Pharmacodynamics and side effects of flecainide acetate. Clinical Pharmacology and Therapeutics 1986, 40:101-107.
14. Starmer C.F., Grant A.O., Colatsky T.J. What happens when cardiac Na channel function is compromised? 2. Numerical studies of the vulnerable period in tissue altered by drugs. Cardiovascular Research 2003, 57:1062-1071.
15. Starmer C.F., Lancaster A.R., Lastra A.A., Grant A.O. Cardiac instability amplified by use-dependent Na channel blockade. The American Journal of Physiology 1992, 262:H1305-H1310.
16. Takanaka C., Lee J.K., Nonokawa M., Sugiyama T., Yame S. Frequency dependent effects of class I antiarrhythmic agents studied in patients with implanted pacemakers. Pacing and Clinical Electrophysiology 1994, 17:2100-2105.
17. Tenneze L., Tarral E., Ducloux N., Funck-Brentano C. Pharmacokinetics and electrocardiographic effects of a new controlled-release form of flecainide acetate: Comparison with the standard form and influence of the CYP2D6 polymorphism. Clinical Pharmacology and Therapeutics 2002, 72:112-122.
18. Zordan R., Padrini R., Bernini V., Piovan D., Ferrari M. Influence of age and gender on the in vitro serum protein binding of flecainide. Pharmacological Research 1993, 28:259-264.