11 March 2022 | Friday | News
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Dr. Sara Kim, Assistant Professor in the Department of Pharmaceutics, and Professor Emeritus Dr. Lawrence Lesko led the research collaboration. With nearly 20 years of experience directing Clinical Pharmacology at the U.S. FDA, Dr. Lesko is a renowned systems pharmacologist and Founding Director of the Center for Pharmacometrics and Systems Pharmacology at the University of Florida in Lake Nona. He emphasizes the importance of this work: “Registries of adverse events constitute a diverse, massive and valuable data source that has not been tapped into to generate and assess molecular hypotheses about causality. The expansion of adverse event information coupled with biological and chemical data, as demonstrated in these studies, is an improvement over traditional pharmacovigilance and can inform future clinical trial designs and personalized medicine.”
Merging molecular knowledge with post-marketing adverse event reports to assess drug safety
The first proof-of-concept study, published in Clinical and Translational Science (CTS), analyzed mechanistic hypotheses in light of cardiotoxicity reports from patients on trastuzumab (Herceptinᴿ) combined with one of four other medications. A monoclonal antibody, trastuzumab targets HER2 and is used to treat breast cancer and advanced stomach cancer. Corroborated with experimental findings in the literature, the study suggested that trastuzumab-induced cardiotoxicity may be enhanced by doxorubicin via mitochondria dysfunction in cardiomyocytes, whereas the combination with tamoxifen, paroxetine, or lapatinib may diminish the undesirable effect by increasing antioxidant activities.
The second proof-of-concept study, published in CTS: Clinical and Translational Science, investigated autoimmunity associated with immunotherapies. The immune checkpoint inhibitors ipilimumab, nivolumab, and pembrolizumab are used for a broad range of cancers and treatment is often accompanied by severe colitis. Results of this study revealed that differences in mode of action – ipilimumab inhibits CTLA-4 whereas nivolumab and pembrolizumab target PD-1 – accounted for a three-fold higher reporting rate of colitis linked to ipilimumab. Mapping chemical and biological data to adverse events reports suggested that ipilimumab may unblock the immune response earlier, leading to heightened T-cell activation.