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An Integrative Appr...
An Integrative Approach for Improved Assessment of Cardiovascular Safety Data
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- Wallman, Mikael, 1979 (author)
- Stiftelsen Fraunhofer-Chalmers Centrum för Industrimatematik (FCC),Fraunhofer-Chalmers Research Centre for Industrial Mathematics (FCC)
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- Scheuerer, Stefan (author)
- Boehringer Ingelheim Pharma GmbH
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- Martel, Eric (author)
- Boehringer Ingelheim Pharma GmbH
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- Pairet, Nicolas (author)
- Boehringer Ingelheim Pharma GmbH
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- Jirstrand, Mats, 1968 (author)
- Chalmers tekniska högskola,Chalmers University of Technology
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Gabrielsson, Johan (author)
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(creator_code:org_t)
- 2021-03-01
- 2021
- English.
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In: Journal of Pharmacology and Experimental Therapeutics. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 1521-0103 .- 0022-3565. ; 377:2, s. 218-231
- Related links:
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https://jpet.aspetjo...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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.
Subject headings
- NATURVETENSKAP -- Matematik -- Annan matematik (hsv//swe)
- NATURAL SCIENCES -- Mathematics -- Other Mathematics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
- NATURVETENSKAP -- Kemi -- Organisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Organic Chemistry (hsv//eng)
Keyword
- cardiovascular drugs
- pharmacokinetic/pharmacodynamic modeling/PKPD
- adverse drug reactions
- computer modeling and simulation
- safety pharmacology
- cardiac toxicity
Publication and Content Type
- art (subject category)
- ref (subject category)
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