Systems Pharmacology of Adverse Event Mitigation by Drug Combinations

Zhao S, Nishimura T, Chen Yb, Azeloglu EU, Gottesman O, Giannarelli C, Zafar MU, Benar L, Badimon JJ, Hajjar RJ, Goldfarb J and Iyengar R. Sci Transl Med 2013 Oct 9; 5 (206) 206ra140


Drugs are designed for therapy, but medication-related adverse events are common and risk/benefit analysis is critical for determining clinical use. Rosiglitazone, an efficacious antidiabetic drug, is associated with increased myocardial infarctions (MI), thus limiting its usage. Because diabetic patients are often prescribed multiple drugs, we searched for usage of a second drug ("drug-B") in the FDA-Adverse Event Reporting System (FAERS) that could mitigate the risk of rosiglitazone ("drug-A")-associated MI. In FAERS, rosiglitazone usage is associated with increased occurrence of MI, but combination with exenatide significantly reduces rosiglitazoneassociated MI. Clinical data from the Mount Sinai Data Warehouse support the observations from FAERS. Analysis for confounding factors using logistic regression showed that they were not responsible for the observed effect. Using cell biological networks, we predicted that the mitigating effect of exenatide on rosiglitazone-associated MI could occur through clotting regulation. Data we obtained from the db/db mouse model agreed with the network prediction. To determine if polypharmacology could generally be a basis for adverse event mitigation, we analyzed the FAERS database for other drug combinations wherein drug-B reduced serious adverse events reported with drug-A usage such as anaphylactic shock and suicidality, associated with drug-A. This analysis revealed 19,133 combinations that could be further studied. We conclude that this type of crowdsourced approach of using databases like FAERS, can help to identify drugs that could potentially be repurposed for mitigation of serious adverse events.

Final Accepted Manuscript

Supplementary Materials

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