A strategy for the risk assessment of human genotoxic metabolites

The role of metabolism in genotoxicity and carcinogenicity of many chemicals is well established. Accordingly, both in vitro metabolic activation systems and in vivo assays are routinely utilized for genotoxic hazard identification of drug candidates prior to clinical investigations. This should, in most cases provide a high degree of confidence that the genotoxic potential of the parent and associated metabolites have been characterized. However, it is well known that significant differences can exist between human metabolism and that which occurs with in vitro and in vivo genotoxicity tests. This poses challenges when considering the adequacy of hazard identification and cancer risk assessment if a human metabolite of genotoxic concern is identified during the course of drug development. Since such challenges are particularly problematic when recognized in the later stages of drug development, a framework for conducting a carcinogenic risk assessment for human genotoxic metabolites is desirable. Here, we propose a risk assessment method that is dependent upon the availability of quantitative human and rodent ADME (absorption, distribution, metabolism, excretion) data, such that exposures to a metabolite of genotoxic concern can be estimated at the intended human efficacious dose and the maximum dose used in the 2-year rodent bioassay(s). The exposures are then applied to the risk assessment framework, based on known cancer potencies, that allows one to understand the probability of a known or suspect genotoxic metabolite posing a carcinogenic risk in excess of 1 in 100,000. Practical case examples are presented to illustrate the application of the risk assessment method within the context of drug development and to highlight its utility and limitations.