An Integrative Approach for Improved Assessment of Cardiovascular Safety Data

M. Wallman, S. Scheuerer, E. Martel, N. Pairet, M. Jirstrand, J. Gabrielsson. Journal of Pharmacology and Experimental Therapeutics, JPET-AR-2020-000348. 1 March 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.

Significance Statement A model-based approach was proposed utilizing biomarker data on heart rate, blood pressure and QT-interval. A pharmacodynamic model was developed to improve assessment of high-resolution telemetric cardiovascular safety data, driven by different drugs (ivabradine, sildenafil, dofetilide, and pimobondan), where system (turnover rates) and drug specific parameters (e.g., potencies and efficacies) were sought. The model predicted equilibrium concentration-biomarker response relationships, and was used for safety assessment (predictions of e.g., EC20) of heart rate, blood pressure, and QT-interval).

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