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A general pharmacodynamic interaction model identifies perpetrators and victims in drug interactions
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 2129Article in journal (Refereed) Published
Abstract [en]

Assessment of pharmacodynamic (PD) drug interactions is a cornerstone of the development of combination drug therapies. To guide this venture, we derive a general pharmacodynamic interaction (GPDI) model for ≥2 interacting drugs that is compatible with common additivity criteria. We propose a PD interaction to be quantifiable as multidirectional shifts in drug efficacy or potency and explicate the drugs’ role as victim, perpetrator or even both at the same time. We evaluate the GPDI model against conventional approaches in a data set of 200 combination experiments in Saccharomyces cerevisiae: 22% interact additively, a minority of the interactions (11%) are bidirectional antagonistic or synergistic, whereas the majority (67%) are monodirectional, i.e., asymmetric with distinct perpetrators and victims, which is not classifiable by conventional methods. The GPDI model excellently reflects the observed interaction data, and hence represents an attractive approach for quantitative assessment of novel combination therapies along the drug development process.

Place, publisher, year, edition, pages
2017. Vol. 8, article id 2129
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-339790DOI: 10.1038/s41467-017-01929-yISI: 000417906800001PubMedID: 29242552OAI: oai:DiVA.org:uu-339790DiVA, id: diva2:1181855
Funder
Swedish Research Council, 521-2011-3442EU, FP7, Seventh Framework Programme, 115337Available from: 2018-02-09 Created: 2018-02-09 Last updated: 2018-02-09Bibliographically approved

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