Role of systems pharmacology in understanding drug adverse events

Abstract

Systems pharmacology involves the application of systems biology approaches, combining largescale experimental studies with computational analyses, to the study of drugs, drug targets, and drug effects. Many of these initial studies have focused on identifying new drug targets, new uses of known drugs, and systems-level properties of existing drugs. This review focuses on systems pharmacology studies that aim to better understand drug side effects and adverse events. By studying the drugs in the context of cellular networks, these studies provide insights into adverse events caused by off-targets of drugs as well as adverse events-mediated complex network responses. This allows rapid identification of biomarkers for side effect susceptibility. In this way, systems pharmacology will lead to not only newer and more effective therapies, but safer medications with fewer side effects.The clinical usefulness of a medication is related to its efficacy in treating specified diseases as well as its safety and tolerability in patients. It is important to understand not only the intended effects of a drug, but also the side effects and potential adverse events associated with treatment. While initial studies of drugs aim to elucidate mechanism of action and therapeutic effects, concerns over potential adverse events can prevent drugs from reaching the market and has led to several high-profile post-market drug failures. Systems pharmacology studies, which integrate large data sets such as protein-protein interaction networks and the FDA adverse event reports with computational analyses, can enhance the understanding of drug adverse events by looking at the effects of a drug in the context of cellular networks as well as exploring relationships between drugs. This can allow better understanding of adverse event pathogenesis and individual patient susceptibility to side effects, as well as identification of new targets. Identification of additional targets (offtargets) for drugs can subsequently lead to improved drug development to decrease offtarget effects and potential repurposing of existing drugs for different diseases. We have previously surveyed the network-based computational techniques used in systems pharmacology studies 1 and reviewed how systems pharmacology approaches are helping direct the evolution toward personalized medicine 2,3 and directing drug discovery. 3,4 This review discusses different ways in which drug side effects and adverse events arise in the context of cellular networks and recent advances in understanding these pathological processes arising from systems pharmacology studies of drug structures, targets, and their relationships to signaling networks that regulate both therapeutic and adverse biological responses (Figure 1).

Logic-Based and Cellular Pharmacodynamic Modeling of Bortezomib Responses in U266 Human Myeloma Cells

“…Despite extensive qualitative information on bortezomib-induced intracellular signaling, mathematical models linking bortezomib exposure to intracellular protein dynamics have not been established. Systems-level modeling may facilitate the rational design of single and combinatorial dosing regimens, approaches to overcome drug resistance, and prevent suboptimal dosing (Berger and Iyengar, 2011;Zhao and Iyengar, 2012). Mechanistic models are emerging in which chemotherapy exposure is connected to ultimate responses through target occupancy and biomarker signal transduction (Yamazaki et al, 2011;Harrold et al, 2012;Kay et al, 2012;Kirouac et al, 2013).…”

On Different Aspects of Network Analysis in Systems Biology

“…Studies of offtarget effects can lead to successful drug repurposing [134,135] or to the prevention of adverse side effects. For instance, blocking of the hERG potassium channel is responsible for many severe drug-induced cardiac arrhythmias and is therefore included as a part of safety testing in drug development [136].…”

Chemical-protein interactome and its application in off-target identification

“…However, examples of such positive outcome are relatively few and are out-numbered by adverse drug effects (Berger and Iyengar, 2010;Wallach et al, 2010) and/or inefficacy (e.g., non-responsive tumors to anticancer drugs), some with fatal outcomes. For example, undesired binding to the hERG channel (Raschi et al, 2009) and 5-HT2B ) receptor can result in fatal heart dysfunctions (long QT syndrome and cardiac fibrosis respectively).…”