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Previously, a two\u2010receptor one\u2010transducer (2R\u20101T) model was proposed to characterize drug interactions with two receptors that lead to the same phenotypic response through a common transducer pathway. We applied, for the first time, the 2R\u20101T model to characterize the interaction of noradrenaline and arginine\u2010vasopressin on vasoconstriction and performed inter\u2010species scaling to humans using this mechanism\u2010based model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Contractile data were obtained from<jats:italic>in vitro<\/jats:italic>rat small mesenteric arteries after exposure to single or combined challenges of noradrenaline and arginine\u2010vasopressin with or without pretreatment with the irreversible \u03b1\u2010adrenoceptor antagonist, phenoxybenzamine. Data were analysed using the 2R\u20101T model to characterize the observed exposure\u2013response relationships and drug\u2013drug interaction. The model was then scaled to humans by accounting for differences in receptor density.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>With receptor affinities set to published values, the 2R\u20101T model satisfactorily characterized the interaction between noradrenaline and arginine\u2010vasopressin in rat small mesenteric arteries (relative standard error \u226420%), as well as the effect of phenoxybenzamine. Furthermore, after scaling the model to human vascular tissue, the model also adequately predicted the interaction between both agents on human renal arteries.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>The 2R\u20101T model can be of relevance to quantitatively characterize the interaction between two drugs that interact<jats:italic>via<\/jats:italic>different receptors and a common transducer pathway. Its mechanistic properties are valuable for scaling the model across species. This approach is therefore of significant value to rationally optimize novel combination treatments.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14385","type":"journal-article","created":{"date-parts":[[2018,6,2]],"date-time":"2018-06-02T17:44:18Z","timestamp":1527961458000},"page":"3394-3406","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Quantitative systems pharmacology analysis of drug combination and scaling to humans: the interaction between noradrenaline and vasopressin in vasoconstriction"],"prefix":"10.1111","volume":"175","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9924-6040","authenticated-orcid":false,"given":"Anyue","family":"Yin","sequence":"first","affiliation":[{"name":"Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research (LACDR) Leiden University Leiden The Netherlands"},{"name":"Department of Clinical Pharmacy and Toxicology Leiden University Medical Centre Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akihiro","family":"Yamada","sequence":"additional","affiliation":[{"name":"Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research (LACDR) Leiden University Leiden The Netherlands"},{"name":"Clinical Pharmacology PKMS Group Astellas Pharma Inc. 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