The FDA detailed how and when drug sponsors should evaluate the nonclinical toxicity of drug metabolites in a final guidance.
In nonclinical studies, sponsors may need to identify the byproducts of the body breaking down a drug when they are “disproportionate,” the agency said.
Disproportionate metabolites include those identified only in humans, or that are present in higher concentrations in humans than in any animal species used in a drug’s nonclinical toxicology testing. Safety concerns should be raised for human metabolites present at greater than 10 percent of total drug-related exposure, the agency said.
A metabolite found in animal tests that isn’t present in humans may mean toxicity caused by that metabolite is not relevant for humans. On the other hand, a drug metabolite that isn’t seen in animal tests or is present at much lower levels in animals than in humans may mean the sponsor should conduct further animal studies.