Tuesday, September 26
Plenary Lecture 2: Making Drugs Great Again: Eliminating Idiosyncratic Drug Reactions
Jack Uetrecht, University of Toronto
Idiosyncratic Drug Reactions (IDRs) significantly increase the risk of drug development. There are two possible solutions to the problem: predicting which drug candidates are likely to be associated with a significant risk of IDRs (designing safer drugs) or predicting which patients are likely to be affected (designing safer patients). With the exception of a few cases in which there is a very strong HLA association such as abacavir hypersensitivity reactions, at the present time there does not appear to be a method to accurately determine which patients are at substantially higher risk. There are several mechanistic hypotheses that have led to strategies to screen drug candidates for IDR risk; however, it is exceedingly difficult to study IDRs, and little is known with certainty. Therefore, the routine use of such strategies is problematic at the present time. These hypotheses include: reactive metabolite formation which leads to an adaptive immune response, reversible binding to immune cells leading to an immune response (p-i hypothesis and altered presentation of endogenous peptides), inflammagen hypothesis, mitochondrial injury, BSEP inhibition, ER stress response, and cell injury leading to the release of DAMPS (danger associated molecular pattern molecules) that activate an immune response. These hypotheses are not mutually exclusive, i.e. a reactive metabolite could both form a neoantigen and cause mitochondrial injury, ER stress, or DAMP release, which, in combination, could lead to a pathogenic immune response. Reactive metabolite formation leading to an adaptive immune response has the best supportive evidence, but not all drugs that cause IDRs appear to form reactive metabolites, and quantifying reactive metabolite formation is not trivial. There is good evidence that abacavir hypersensitivity reactions involve altered endogenous peptide presentation, but this does not appear to be a common mechanism, and it would be difficult to screen drug candidates for this mechanism. The inflammagen hypothesis is not consistent with clinical observations. There is strong evidence that a few IDRs, such as valproate-induced liver injury involve mitochondrial injury; however, most evidence does not support this as a general IDR mechanism. BSEP inhibition and ER stress are plausible hypotheses, but lack sufficient evidence to provide confidence that they are generally important. There is recent evidence that the release of DAMPs may be a important indication of IDR risk, but it is too early to be confident that this is a general mechanism. In the past it has been virtually impossible to rigorously test hypotheses; however, impairing immune tolerance has led to in vivo animal models that make it possible to test hypotheses that have not been possible to test in the past. I am optimistic that significant progress will be made in the development of better methods to predict IDR risk; however, real progress will require extensive basic mechanistic studies, and it may never be possible to completely prevent IDRs.