Reactive Metabolite Assessment in Drug Discovery and Development in Support of Safe Drug Design

Abstract

The contribution of chemically reactive metabolites to drug-induced liver injury and other immune-mediated serious adverse drug reactions has been acknowledged as an important determinant of drug failure. Reasons for individual susceptibilities of patients that result in various forms and severities of adverse drug reactions are manifold. They involve factors such as the underlying diseases, individual genotypes of the immune system, and drug specific risk factors. Likewise, the characterizing of drug metabolizing pathways leading to bioactivation and reactive metabolite formation covalently modifying cellular macromolecules alone has been proven unsuccessful in relating bioactivation to adverse drug reactions. The emergence of sensitive and specific mass spectrometry methods has led to a myriad of experimental approaches trying to establish a causal link between reactive metabolite formation and drug-induced liver injury. Many of these failed. The main two reasons are: (1) Methods are overly sensitive or unspecific and flag many drugs that show a safe history of use in a large population. (2) Reactive metabolite screening methods are too generic and fail to detect drug-specific bioactivation pathways requiring alternative experimental approaches. As a consequence, testing paradigms that integrate knowledge of bioactivation pathways based on chemical structures (structural alerts), chemotype-specific experimental tools for reactive metabolite characterization, and the quantitative assessment of bioactivation pathways relative to “safe” metabolism and dose have emerged. Such strategies that characterize bioactivation potentials in the context of drug metabolism, pharmacokinetic properties, clinical dose and additional risk factors have been proposed and successfully applied across the pharmaceutical industry. Case studies and examples for successful risk assessment strategies and general principles to guide safe drug design are discussed in this chapter.