{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T12:11:37Z","timestamp":1788523897133,"version":"build-2803163510"},"reference-count":29,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2022,3,18]],"date-time":"2022-03-18T00:00:00Z","timestamp":1647561600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The use of systems\u2010based pharmacological modeling approaches to characterize mode\u2010of\u2010action and concentration\u2010effect relationships for drugs on specific hemodynamic variables has been demonstrated. Here, we (i) expand a previously developed hemodynamic system model through integration of cardiac output (CO) with contractility (CTR) using pressure\u2010volume loop theory, and (ii) evaluate the contribution of CO data for identification of system\u2010specific parameters, using atenolol as proof\u2010of\u2010concept drug. Previously collected experimental data was used to develop the systems model, and included measurements for heart rate (HR), CO, mean arterial pressure (MAP), and CTR after administration of atenolol (0.3\u201330\u00a0mg\/kg) from three in vivo telemetry studies in conscious Beagle dogs. The developed cardiovascular (CVS)\u2010contractility systems model adequately described the effect of atenolol on HR, CO, dP\/dtmax, and MAP dynamics and allowed identification of both system\u2010 and drug\u2010specific parameters with good precision. Model parameters were structurally identifiable, and the true mode of action can be identified properly. Omission of CO data did not lead to a significant change in parameter estimates compared to a model that included CO data. The newly developed CVS\u2010contractility systems model characterizes short\u2010term drug effects on CTR, CO, and other hemodynamic variables in an integrated and quantitative manner. When the baseline value of total peripheral resistance is predefined, CO data was not required to identify drug\u2010 and system\u2010specific parameters. Confirmation of the consistency of system\u2010specific parameters via inclusion of data for additional drugs and species is warranted. Ultimately, the developed model has the potential to be of relevance to support translational CVS safety studies.<\/jats:p>","DOI":"10.1002\/psp4.12774","type":"journal-article","created":{"date-parts":[[2022,2,25]],"date-time":"2022-02-25T20:45:14Z","timestamp":1645821914000},"page":"640-652","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A novel cardiovascular systems model to quantify drugs effects on the inter\u2010relationship between contractility and other hemodynamic variables"],"prefix":"10.1002","volume":"11","author":[{"given":"Yu","family":"Fu","sequence":"first","affiliation":[{"name":"Leiden Academic Centre for Drug Research Leiden University  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hadi","family":"Taghvafard","sequence":"additional","affiliation":[{"name":"Leiden Academic Centre for Drug Research Leiden University  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Medhat M.","family":"Said","sequence":"additional","affiliation":[{"name":"Leiden Academic Centre for Drug Research Leiden University  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric I.","family":"Rossman","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline  Collegeville Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa A.","family":"Collins","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology Clinical Pharmacology and Safety Sciences R&amp;D, AstraZeneca  Royston UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phanie","family":"Billiald\u2010Desquand","sequence":"additional","affiliation":[{"name":"Servier  Suresnes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek","family":"Leishman","sequence":"additional","affiliation":[{"name":"Elly Lilly and Company  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piet H.","family":"van der Graaf","sequence":"additional","affiliation":[{"name":"Leiden Academic Centre for Drug Research Leiden University  Leiden The Netherlands"},{"name":"Certara QSP  Canterbury UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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