An Integrative Approach for Improved Assessment of Cardiovascular Safety Data
Journal article, 2021

Cardiovascular adverse effects in drug development are a major source of compound attrition. Characterization of blood pressure (BP), heart rate (HR), stroke volume (SV), and QT-interval prolongation are therefore necessary in early discovery. It is, however, common practice to analyze these effects independently of each other. High-resolution time courses are collected via telemetric techniques, but only low-resolution data are analyzed and reported. This ignores co-dependencies among responses (HR, BP, SV, and QT-interval) and separation of system (turnover properties) and drug-specific properties (potencies, efficacies). An analysis of drug exposure-time and high-resolution response-time data of HR and mean arterial blood pressure was performed after acute oral dosing of ivabradine, sildenafil, dofetilide and pimobendan in Han-Wistar rats. All data were modelled jointly including different compounds, exposure- and response-time courses using a non-linear mixed effects-approach. Estimated fractional turnover rates (h-1, %RSE within brackets) were 9.45 (15), 30.7 (7.8), 3.8 (13) and 0.115 (1.7) of QT, HR, TPR and SV, respectively. Potencies (nM, %RSE within brackets) were IC50=475 (11), IC50=4.01 (5.4), EC50=50.6 (93) and IC50=47.8 (16), and efficacies (%RSE within brackets) were Imax=0.944 (1.7), Imax=1.00 (1.3), Emax=0.195 (9.9), and Imax=0.745 (4.6) for ivabradine, sildenafil, dofetilide and pimobendan. Hill-parameters were estimated with good precision, and below unity, indicating a shallow concentration-response relationship. An equilibrium concentration-biomarker response relationship was predicted and displayed graphically. This analysis demonstrates the utility of a model-based approach, integrating data from different studies and compounds, for refined pre-clinical safety margin assessment.

safety pharmacology

adverse drug reactions

computer modeling and simulation

cardiac toxicity

pharmacokinetic/pharmacodynamic modeling/PKPD

cardiovascular drugs

Author

Mikael Wallman

Stefan Scheuerer

Boehringer Ingelheim

Eric Martel

Boehringer Ingelheim

Nicolas Pairet

Boehringer Ingelheim

Mats Jirstrand

Chalmers, Electrical Engineering, Systems and control

Johan Gabrielsson

Firma Biopharmacon

Journal of Pharmacology and Experimental Therapeutics

0022-3565 (ISSN) 1521-0103 (eISSN)

Areas of Advance

Information and Communication Technology

Health Engineering

Roots

Basic sciences

Subject Categories

Other Mathematics

Pharmacology and Toxicology

Organic Chemistry

DOI

10.1124/jpet.120.000348

More information

Created

3/12/2021