An Integrative Approach for Improved Assessment of Cardiovascular Safety Data
| Autor: | Mats Jirstrand, Stefan Scheuerer, Mikael Wallman, Eric Martel, Johan Gabrielsson, Nicolas Pairet |
|---|---|
| Přispěvatelé: | Publica |
| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Blood Pressure Dofetilide Biomarkers Pharmacological Sildenafil Citrate 03 medical and health sciences 0302 clinical medicine Heart Rate Internal medicine Phenethylamines Heart rate medicine Animals Ivabradine Rats Wistar Pharmacology Sulfonamides business.industry Safety pharmacology Cardiovascular Agents Stroke volume Cardiotoxicity Rats Pyridazines 030104 developmental biology Blood pressure Pimobendan Pharmacodynamics Cardiology Molecular Medicine business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 377:218-231 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | 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 codependencies 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 modeled jointly, including different compounds and exposure and response time courses, using a nonlinear mixed-effects approach. Estimated fractional turnover rates [h-1, relative standard error (%RSE) within parentheses] were 9.45 (15), 30.7 (7.8), 3.8 (13), and 0.115 (1.7) for QT, HR, total peripheral resistance, and SV, respectively. Potencies (nM, %RSE within parentheses) were IC 50 = 475 (11), IC 50 = 4.01 (5.4), EC 50 = 50.6 (93), and IC 50 = 47.8 (16), and efficacies (%RSE within parentheses) were I max = 0.944 (1.7), Imax = 1.00 (1.3), E max = 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 preclinical 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), wherein 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 20% effective concentration, for example) of heart rate, blood pressure, and QT-interval. |
| Databáze: | OpenAIRE |
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