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Evaluating the Application of the BDDCS to Assess the Risk of Skin and Liver Toxicity Potential in Small Molecules Using In Vitro and Human Clinical Data

  • Author(s): Chan, Rosa
  • Advisor(s): Benet, Leslie Z
  • et al.
Abstract

Drug hypersensitivity can be defined as a serious adverse drug reaction (ADR) often with an immunological etiology to an otherwise safe and effective therapeutic agent. The frequency and severity of drug hypersensitivity are variable, increasing with disease and dose. Hence, it is important to understand the biology of the patient/immune system, the pathophysiology of the disease in question, and the chemistry of the drug antigen.

The objective of this research project is to advance the understanding of drug toxicities associated with the liver and the skin, the two organs most commonly involved in serious adverse drug reactions by investigating the potential of the Biopharmaceutics Drug Disposition Classification System (BDDCS) as a methodology for evaluating toxicological outcome of therapeutic agents.

One of the key gaps moving forward is our understanding of and ability to predict the contribution of immune activation in idiosyncratic adverse drug reactions. This work will focus on immune mediated idiosyncratic adverse drug reactions associated with HLA-B*15:02 and on the presently proposed/hypothesized in vitro mechanism based toxicity mechanisms for drug-induced liver injury (DILI). The advances being made in microphysiological systems have a great potential to transform our ability to risk assess reactive metabolites, and an overview of the key components of these systems are presented.

Our published analyses suggest that comparison of drug hypersensitivity prediction methodologies with BDDCS classification is a useful tool to evaluate the potential reliability of newly proposed algorithms. This is true since almost all of these predictive metrics do no better than just avoiding BDDCS Class 2 drugs.

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