Skip to main content

ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Predictive Toxicology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1402462
This article is part of the Research Topic Advances and Applications of Predictive Toxicology in Knowledge Discovery, Risk Assessment, and Drug Development View all 7 articles

Modelling hemodynamics regulation in rats and dogs to facilitate drugs safety risk assessment

Provisionally accepted
Christopher J. Morris Christopher J. Morris 1,2Mike Rolf Mike Rolf 3Linda Starnes Linda Starnes 3Conchi Villar Moas Conchi Villar Moas 4Giovanni Y. Di Veroli Giovanni Y. Di Veroli 2*
  • 1 AstraZeneca (United Kingdom), London, England, United Kingdom
  • 2 AstraZeneca, Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Science, Cambridge, United Kingdom
  • 3 AstraZeneca, Safety Sciences, Clinical Pharmacology and Safety Science, Gothenburg, Sweden
  • 4 AstraZeneca, Safety Sciences, Clinical Pharmacology and Safety Science, Cambridge, United Kingdom

The final, formatted version of the article will be published soon.

    Pharmaceutical companies routinely screen compounds for hemodynamics related safety risk. In vitro secondary pharmacology is initially used to prioritize compounds while in vivo studies are later used to quantify and translate risk to humans. This strategy has shown limitations but could be improved via the incorporation of molecular findings in the animal-based toxicological risk assessment. The aim of this study is to develop a mathematical model for rat and dog species that can integrate secondary pharmacology modulation and therefore facilitate the overall pre-clinical safety translation assessment. Following an extensive literature review, we built two separate models recapitulating known regulation processes in dogs and rats. We describe the resulting models and show that they can reproduce a variety of interventions in both species. We also show that the models can incorporate the mechanisms of action of a pre-defined list of 50 pharmacological mechanisms whose modulation predict results consistent with known pharmacology. In conclusion, a mechanistic model of hemodynamics regulations in rat and dog species has been developed to support mechanism-based safety translation in drug discovery and development.

    Keywords: Hemodynamic drug safety, clinical translation, Quantitative systems toxicology, rat, dog, secondary pharmacology, Telemetry, Cardiovascular safety

    Received: 17 Mar 2024; Accepted: 28 Aug 2024.

    Copyright: © 2024 Morris, Rolf, Starnes, Villar Moas and Di Veroli. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Giovanni Y. Di Veroli, AstraZeneca, Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Science, Cambridge, United Kingdom

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.