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PKPD modelling of PR and QRS intervals in conscious dogs using standard safety pharmacology data
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Bergenholm, Linnéa, Collins, Teresa, Evans, Neil D., Chappell, M. J. (Michael J.) and Parkinson, Joanna (2016) PKPD modelling of PR and QRS intervals in conscious dogs using standard safety pharmacology data. Journal of Pharmacological and Toxicological Methods, 79 . pp. 34-44. doi:10.1016/j.vascn.2016.01.002 ISSN 1056-8719.
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Official URL: http://dx.doi.org/10.1016/j.vascn.2016.01.002
Abstract
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 antiarrhythmic 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 antimuscarinics. 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 verapamil were best described by Emax 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.
Item Type: | Journal Article | ||||||||||
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Subjects: | R Medicine > RS Pharmacy and materia medica | ||||||||||
Divisions: | Faculty of Science, Engineering and Medicine > Engineering > Engineering | ||||||||||
Library of Congress Subject Headings (LCSH): | Drugs -- Analysis | ||||||||||
Journal or Publication Title: | Journal of Pharmacological and Toxicological Methods | ||||||||||
Publisher: | Elsevier Inc. | ||||||||||
ISSN: | 1056-8719 | ||||||||||
Official Date: | May 2016 | ||||||||||
Dates: |
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Volume: | 79 | ||||||||||
Number of Pages: | 11 | ||||||||||
Page Range: | pp. 34-44 | ||||||||||
DOI: | 10.1016/j.vascn.2016.01.002 | ||||||||||
Status: | Peer Reviewed | ||||||||||
Publication Status: | Published | ||||||||||
Access rights to Published version: | Restricted or Subscription Access | ||||||||||
Date of first compliant deposit: | 15 February 2016 | ||||||||||
Funder: | Seventh Framework Programme (European Commission) (FP7), AstraZeneca (Firm), Pulmagen Therapeutics (Firm) | ||||||||||
Grant number: | 316736 (FP7) |
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