Grant: Project Grant

Adverse drug reactions are a significant problem. One type, called idiosyncratic drug reactions (IDRs), do not occur in most patients but can be life threatening when they do occur. Their unpredictable nature makes them a major problem for patients, drug development, and for regulatory agencies. Because they are very unpredictable, they are very difficult to study. There is a large amount of evidence that they are mediated by the immune system. This is analogous to how most people are not allergic to peanuts, but the allergy can be fatal for people who are allergic. Although most patients do not have a serious reaction when they take drugs that can cause IDRs, there is evidence that most patients and animals do have an immune response, called an innate immune response. This innate response happens early, causes no symptoms, and usually resolves on its own. It is only when the innate immune response leads to an adaptive immune response that a serious IDR occurs. The adaptive immune response is dependent on genetics and previous exposure to other agents, which is why, like other allergies, it is idiosyncratic. It is this initial asymptomatic innate immune response to drugs that can cause serious IDRs that we will study, first in animals and then in humans. With a better understanding of this innate immune response we should be able to predict which drug candidates are likely to cause serious IDRs and which patients may be at risk. In addition, a better mechanistic understanding may lead to ways to treat patients experiencing IDRs, or even prevent them altogether. Ultimately, these studies are likely to lead to increased drug safety and decreased health care costs. Already our mechanistic studies have led to a method to prevent severe adverse reactions to a new anti-seizure medication, which led to its approval by the US Food and Drug Administration. I am also consulting for another company to improve the safety of another drug.