Will my compounds induce adverse drug reactions?

Predicting adverse drug reactions

Any adverse drug reaction (ADR) which arises during clinical development or clinical use of a compound can seriously jeopardise its continued development or use. This is not surprising as ADRs have been estimated to be the fourth leading cause of death in the US (100,000 deaths per year), and drug induced illness as a result of ADR are estimated to cost US$136 billion per year. Strategies that reduce these statistics will therefore have considerable medical, social, and economic benefits.

The CXR approach

CXR Biosciences aims to accurately predict and screen out compounds that are likely to cause adverse drug reactions. Many ADRs are idiosyncratic and these may be difficult, if not impossible, to predict. However the in depth understanding of mechanistic toxicology and ADME at CXR Biosciences means that we are able to predict mechanism-based ADRs with some confidence. Through mechanistic understanding, strategies can be developed to minimise the risk of further ADR’s and hence obviate the expense of compound withdrawal. Understanding the mechanisms underlying ADRs can also predict the risk of further exacerbation or induction of ADRs due to environmental exposure.

To date, the majority of mechanism-based ADRs have proved to be mediated by inhibition of key drug metabolising enzymes (usually of the cytochrome P450 family). CXR Biosciences has a well established approach to the prediction of this class of ADRs, using human liver microsomes and recombinant enzymes to determine which isozymes are able to metabolise the candidate and whether any of them are subject to inhibition. By combining this experimental approach with an extensive knowledge of the drug metabolism we are able to accurately predict metabolic ADRs with a good degree of confidence.

Much less is known about the role of drug transporters in ADRs, but it is likely that many such problems are related to inhibition of drug uptake or excretion. CXR Biosciences have developed a range of in vitro assays for drug transport, allowing the possible effects on uptake and excretion as well as metabolism to be considered when evaluating the potential for ADRs.