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.
BACKGROUND
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.


CONCLUSIONS
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.
Nolan
Emily R
ER
Pfizer Global Research and Development, Ann Arbor, MI 48105, USA. emily.nolan@pfizer.com
Feng
Meihua Rose
MR
Koup
Jeffrey R
JR
Liu
Jing
J
Turluck
Daniel
D
Zhang
Yiqun
Y
Paulissen
Jerome B
JB
Olivier
N Bari
NB
Miller
Teresa
T
Bailie
Marc B
MB
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D001283:Atrioventricular Node / Q000601:surgery; D002036:Bundle of His / Q000601:surgery; D002304:Cardiac Pacing, Artificial; D017115:Catheter Ablation; D020117:Cisapride / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004562:Electrocardiography / Q000187:drug effects; D005765:Gastrointestinal Agents / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D006634:Histamine H1 Antagonists / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D007473:Ion Channels / Q000037:antagonists & inhibitors; D008133:Long QT Syndrome / Q000209:etiology*; D008297:Male; D023421:Models, Animal; D008954:Models, Biological; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D016593:Terfenadine / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity
D000889:Anti-Arrhythmia Agents; D005765:Gastrointestinal Agents; D006634:Histamine H1 Antagonists; D007473:Ion Channels; D010880:Piperidines; D011725:Pyridines; C063968:E 4031; D016593:Terfenadine; D020117:Cisapride