A novel predictive pharmacokinetic/pharmacodynamic model of repolarization prolongation derived from the effects of terfenadine, cisapride and E-4031 in the conscious chronic av node—ablated, His bundle-paced dog

• Published in: Journal of pharmacological and toxicological methods Vol. 53; no. 1; pp. 1 - 10
• Main Authors: Nolan, Emily R., Feng, Meihua Rose, Koup, Jeffrey R., Liu, Jing, Turluck, Daniel, Zhang, Yiqun, Paulissen, Jerome B., Olivier, N. Bari, Miller, Teresa, Bailie, Marc B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2006
• Subjects: Animals; Anti-Arrhythmia Agents - blood; Anti-Arrhythmia Agents - pharmacokinetics; Anti-Arrhythmia Agents - toxicity; Atrioventricular Node - surgery; Bundle of His - surgery; Cardiac Pacing, Artificial; Cardiovascular; Catheter Ablation; Cisapride - blood; Cisapride - pharmacokinetics; Cisapride - toxicity; Dog; Dogs; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical - methods; Electrocardiography - drug effects; Gastrointestinal Agents - blood; Gastrointestinal Agents - pharmacokinetics; Gastrointestinal Agents - toxicity; His bundle-pacing; Histamine H1 Antagonists - blood; Histamine H1 Antagonists - pharmacokinetics; Histamine H1 Antagonists - toxicity; Ion Channels - antagonists & inhibitors; Long QT Syndrome - etiology; Male; Methods; Models, Animal; Models, Biological; Pharmacokinetic/pharmacodynamic modeling; Piperidines - blood; Piperidines - pharmacokinetics; Piperidines - toxicity; Pyridines - blood; Pyridines - pharmacokinetics; Pyridines - toxicity; QT interval; Repolarization; Terfenadine - blood; Terfenadine - pharmacokinetics; Terfenadine - toxicity; QT interval; Repolarization; Cardiovascular; His bundle-pacing; Dog; Methods; Pharmacokinetic/pharmacodynamic modeling
• ISSN: 1056-8719; 1873-488X
• DOI: 10.1016/j.vascn.2005.02.003

Introduction: Terfenadine, cisapride, and E-4031, three drugs that prolong ventricular repolarization, were selected to evaluate the sensitivity of the conscious chronic atrioventricular node—ablated, His bundle-paced Dog for defining drug induced cardiac repolarization prolongation. A novel predictive pharmacokinetic/pharmacodynamic model of repolarization prolongation was generated from these data. Methods: Three male beagle dogs underwent radiofrequency AV nodal ablation, and placement of a His bundle-pacing lead and programmable pacemaker under anesthesia. Each dog was restrained in a sling for a series of increasing dose infusions of each drug while maintained at a constant heart rate of 80 beats/min. RT interval, a surrogate for QT interval in His bundle-paced dogs, was recorded throughout the experiment. Results: E-4031 induced a statistically significant RT prolongation at the highest three doses. Cisapride resulted in a dose-dependent increase in RT interval, which was statistically significant at the two highest doses. Terfenadine induced a dose-dependent RT interval prolongation with a statistically significant change occurring only at the highest dose. The relationship between drug concentration and RT interval change was described by a sigmoid E max model with an effect site. Maximum RT change ( E max), free drug concentration at half of the maximum effect (EC 50), and free drug concentration associated with a 10 ms RT prolongation (EC 10 ms) were estimated. A linear correlation between EC 10 ms and HERG IC 50 values was identified. Discussion: The conscious dog with His bundle-pacing detects delayed cardiac repolarization related to I Kr inhibition, and detects repolarization change induced by drugs with activity at multiple ion channels. A clinically relevant sensitivity and a linear correlation with in vitro HERG data make the conscious His bundle-paced dog a valuable tool for detecting repolarization effect of new chemical entities.