Developing in vitro and in vivo Models to Predict Drug-Induced Acute Allergic Adverse Reactions
Thursday, September 17, 2015 — Poster Session III
- ZH Zhou
- S Bupp
- S Kozlowski
All medications have the potential to produce adverse events (AEs). Lower frequency serious AEs, particularly severe life-threatening anaphylaxis that can occur within minutes after drug administration, have been considered significant enough to take drugs off the market. Thus, ideally, premarket studies based on sensitive models would predict rare serious adverse events and could inform marketing decisions and post-market surveillance. From the study of 2008 heparin AEs which caused hundreds of acute hypersensitivity-like symptoms and death to the more recent recall of Omontys (peginesatide) which caused anaphylaxis, our research group has established several in vitro and in vivo models to rapidly evaluate potential causes of an acute anaphylactic reaction. These methods are based upon current understanding of the mechanisms of clinical anaphylaxis, and include: 1) flow cytometry- based drug-specific IgE/IgG screening and in vitro Type 1 sensitization model (using drug-binding antibodies and mast cell degranulation); 2) direct mast cell degranulation; 3) assays for a cytokine storm (using activated T cells and macrophages from PBMC or whole blood culture); 4) complement- activation generated anaphylatoxins assays (C3a, C4a and C5a); and 5) contact system (kinin/kallikrein) activation assays. In addition, we are also developing a C1 inhibitor deficient mouse model to enhance the prediction of contact system- associated acute allergy in vivo. These in vitro and in vivo models will not only help FDA quickly respond to and identify the potential causes of drug-induced acute allergic AEs, but could also facilitate development of safer products by improving the understanding and mitigation of such risks.