PKPD modelling of PR and QRS intervals in conscious dogs using standard safety pharmacology data

Introduction: Pharmacokinetic-pharmacodynamic (PKPD) modelling can improve safety assessment, but few PKPD models describing drug-induced QRS and PR prolongations have been published. This investigation aims to develop and evaluate PKPD models for describing QRS and PR effects in routine safety studies. Methods: Exposure and telemetry data from safety pharmacology studies in conscious beagle dogs were acquired. Mixed effects baseline and PK-QRS/PR models were developed for the anti-arrhythmic compounds AZD1305, flecainide, quinidine and verapamil and the anti-muscarinic compounds AZD8683 and AZD9164. RR interval correction and circadian rhythms were investigated for predicting baseline variability. Individual PK predictions were used to drive the pharmacological effects evaluating linear and non-linear direct and effect compartment models. Results: Conduction slowing induced by the tested anti-arrhythmics was direct and proportional at low exposures, whilst time delays and non-linear effects were evident for the tested anti-muscarinics. AZD1305, flecainide and quinidine induced QRS widening with 4.2, 10 and 5.6% mu M-1 unbound drug. AZD1305 and flecainide also prolonged PR with 13.5 and 11.5% mu M-1. PR prolongations induced by the anti-muscarinics and verapamil were best described by E-max models with maximal effects ranging from 55 to 95%. RR interval correction and circadian rhythm improved PR but not QRS modelling. However, circadian rhythm had minor impact on estimated drug effects. Discussion: Baseline and drug-induced effects on QRS and PR intervals can be effectively described with PKPD models using routine data, providing quantitative safety information to support drug discovery and development. (C) 2016 Elsevier Inc. All rights reserved.