US FDA guidance on safety testing of drug metabolites revised

The US Food and Drug Administration (FDA) recently released revised guidance on recommendations on when and how to evaluate the nonclinical toxicity of drug metabolites. The revisions mean the new guidance is now aligned with the ICH M3(R2) Nonclinical Safety Studies guideline. The guidance represents the consensus that exists regarding the type and duration of nonclinical safety studies and their timing to support the conduct of human clinical trials and marketing authorisations for pharmaceuticals.

Nonclinical evaluation of drug safety normally consists of standard animal toxicology studies, including assessment of drug exposure, primarily by parent drug plasma concentration. Generally, drug plasma concentration and systemic exposure in the nonclinical studies are compared with systemic exposure in humans to assess the potential risks from nonclinical findings and direct the monitoring in clinical trials. The adequacy of this approach is acceptable when the human metabolic profile is similar to at least one of animal species tested in nonclinical studies. If however, the metabolic profiles are different, it is possible that clinically relevant metabolites are not identified or adequately evaluated during nonclinical safety studies. “It is not standard practice for drug metabolites to be evaluated separately in a cross-species safety assessment. As a result, their specific contribution to the overall toxicity of the parent drug has often remained unknown,” FDA says.

The agency says it encourages the identification of any differences in drug metabolism between animals used in nonclinical safety assessments and humans as early as possible in a drug’s development. The discovery of disproportionate drug metabolites late in drug development can potentially extend the time taken for development and registration and thereby cause marketing delays . “Generally, metabolites identified only in human plasma or metabolites present at disproportionately higher levels in humans than in any of the animal test species should be considered for safety assessment” says FDA. Human metabolites that are formed at greater than 10% of total drug-related exposure at steady state require further characterisation and evaluation.

To read the FDA guidance, please click here and to access the ICH M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorisation for Pharmaceuticals guideline and past presentation, click here.