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

Journal of Pharmacological and Toxicological Methods
Linnéa BergenholmJoanna Parkinson

Abstract

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. 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. 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% μM(-1) unbound drug. AZD1305 and flecainide also prolonged PR with 13.5 and 11.5% μM(-1). PR prolongations induced by the anti-muscarinics and verapa...Continue Reading

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Citations

Mar 30, 2017·Pharmacological Reviews·Annabelle BallestaFrancis A Lévi
Jul 5, 2017·British Journal of Pharmacology·L BergenholmT Collins
Dec 21, 2016·Frontiers in Physiology·David L I JanzénMichael J Chappell

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