Improving drug safety with a systems pharmacology approach.
Systems pharmacology is used to mechanistically analyze drug-adverse drug reaction (ADRs) pairs and is a promising solution to the complex problem of understanding mechanisms of toxicity. In this research, we have explored the feasibility of retrospectively mapping population-level adverse events from the FDA Adverse Event Reporting System (FAERS) to chemical and biological databases to identify drug safety signals and the underlying molecular mechanisms. We used an analytic platform - Molecular Analysis of Side Effects (MASE™). For this purpose, we selected the adverse event of severe and potentially fatal cutaneous reactions (SCARs) that are associated with acetaminophen (APAP). SCARs encompass the continuum between Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). We found a statistically significant association between APAP and TEN, the most severe form of SCARs. We also explored the influence of APAP on other classes of drugs commonly associated with SCARs. We found that APAP significantly reduced the risk of SCARs commonly associated with carbamazepine (CBZ). We used molecular docking simulations to propose a mechanism for APAP's reduction in CBZ-induced SCARs which is competitive inhibition of the binding of CBZ to HLA-B*15:02. We conclude that systems pharmacology can complement established surveillance methodologies by providing a means to undertake an independent investigation and review of the mechanisms by which drugs cause adverse events.
The Center for Pharmacometrics and Systems Pharmacology, University of Florida, Orlando, Florida, United States; Office of Clinical Pharmacology, Office of Translational Sciences, US Food and Drug Administration, United States.
Peter
P
Schotland
Molecular Health, Heidelberg, Germany.
Niels
N
Bojunga
Molecular Health, Heidelberg, Germany.
Alexander
A
Zien
The Center for Pharmacometrics and Systems Pharmacology, University of Florida, Orlando, Florida, United States.
Mirjam Nadine
MN
Trame
The Center for Pharmacometrics and Systems Pharmacology, University of Florida, Orlando, Florida, United States. Electronic address: llesko@cop.ufl.edu.
Lawrence J
LJ
Lesko
D000082:Acetaminophen / Q000009:adverse effects / Q000378:metabolism; D016907:Adverse Drug Reaction Reporting Systems; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects; D000927:Anticonvulsants / Q000009:adverse effects; D002220:Carbamazepine / Q000009:adverse effects / Q000378:metabolism; D016208:Databases, Factual; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis / Q000453:epidemiology / Q000517:prevention & control; D006801:Humans; D062105:Molecular Docking Simulation / Q000379:methods*; D010601:Pharmacology, Clinical / Q000379:methods*; D013262:Stevens-Johnson Syndrome / Q000175:diagnosis / Q000453:epidemiology / Q000517:prevention & control; D049490:Systems Biology / Q000379:methods*
D018712:Analgesics, Non-Narcotic; D000927:Anticonvulsants; D002220:Carbamazepine; D000082:Acetaminophen
Drug safety; Informatics; Stevens-Johnson Syndrome; Systems pharmacology