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Annu Rev Pharmacol Toxicol. 2019 Jan 6;59:21-40. doi: 10.1146/annurev-pharmtox-010818-021511. Epub 2018 Sep 27.

Systems Pharmacology: Defining the Interactions of Drug Combinations.

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Department of Pharmacological Sciences, Systems Biology Center, Mount Sinai Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; email:
Division of Systems Biomedicine and Pharmacology, Leiden Academic Center for Drug Research, Leiden University, 2333 Leiden, Netherlands; email:


The majority of diseases are associated with alterations in multiple molecular pathways and complex interactions at the cellular and organ levels. Single-target monotherapies therefore have intrinsic limitations with respect to their maximum therapeutic benefits. The potential of combination drug therapies has received interest for the treatment of many diseases and is well established in some areas, such as oncology. Combination drug treatments may allow us to identify synergistic drug effects, reduce adverse drug reactions, and address variability in disease characteristics between patients. Identification of combination therapies remains challenging. We discuss current state-of-the-art systems pharmacology approaches to enable rational identification of combination therapies. These approaches, which include characterization of mechanisms of disease and drug action at a systems level, can enable understanding of drug interactions at the molecular, cellular, physiological, and organismal levels. Such multiscale understanding can enable precision medicine by promoting the rational development of combination therapy at the level of individual patients for many diseases.


QSP; combination therapy; modeling; pharmacodynamics; quantitative systems pharmacology; systems biology; systems pharmacology

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