RESEARCH & DEVELOPMENT
D
rug Hypersensitivity Reactions (DHRs) belong to type B adverse drug reactions, defined by the World Health Organisation (WHO) as dose-independent, unpredictable, noxious, and unintended response to a drug at dose normally used in humans. They include drug intolerance, drug idiosyncrasy, drug allergy and non-allergic anaphylactic reaction. Most of type B reactions have an immunological basis, including idiosyncratic liver injury, often resembling hypersensitivity reactions. Gomes et al. reported that DHRs represent about one third of adverse drug reactions, overall, affecting 7 per cent of the general population and up to 20 per cent of hospitalised patients. The incidence of drug-induced anaphylaxis has been estimated to range from 0.04 to 3.1 per cent, with an increased rate by 150 per cent from 1997 to 2005. DHRs are responsible for significant morbidity, mortality and socioeconomic costs. Therefore, it will be extremely
important to have tools in the preclinical phase to identify potential drugs having the intrinsic ability to activate an inappropriate immune response to have proper risk management measures in place. Despite the important adverse reactions linked to hypersensitivity, currently in the pre-clinical phase, there are no validated or requested in vivo/in vitro tests to assess the sensitising potential of a drug. This article will focus on low molecular weight drugs, discussing available in vitro tools and challenges in the pre-clinical safety assessment of drug-inducing hypersensitivity reactions. Different it is the case with therapeutic proteins, which possess the structural complexity sufficient to induce a specific immune response, or drug-inducing pseudo-allergic reactions, in which adaptive immune response is not involved. Readers are referred to a recently published article by the same authors on the same topic.
Mechanistic Understanding
Hypersensitivity reactions can be divided in non-allergic (pseudo-anaphylaxis) or allergic when mediated by a specific adaptive immune response. In the latter case, they can be defined as an excessive humoral or cellular immune response to an antigen which can lead to tissue damage or systemic effects. Examples of drug that can induce DHRs include penicillins, cephalosporins, diclofenac, neuromuscular blocking agents, hydralazine, methyldopa, sulphonamides, hydralazine, procainamide, neomycin, carbamazepine, allopurinol, benzocaine, and several biologicals (e.g. rituximab, naglazyme, infliximab). Besides the Gell and Coombs’ classification of hypersensitivity reactions, a simpler classification, very useful in the context of preclinical safety assessment, is to divide drug hypersensitivities in drug allergies with primarily antibodymediated reactions or cell-mediated
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