A summary of recommended actions for metabolites in safety testing
Matrix | Structure of Metabolite | Cutoff | Action |
|---|---|---|---|
| Circulation | Minor change from parent drug (e.g. demethylation, deethylation, hydroxylation, desaturation) | In vitro affinity ≥25% of that of the parent drug | Determine free fraction; if free concentration can contribute 25% of target receptor occupancy, then routinely measure in safety and clinical studies; understand clearance mechanism of the metabolite; understand target organ penetrability |
| Circulation | Major change from parent drug (e.g. conjugation, cleavage into two major portions, N-deamination) | Total concentrations exceed 1 μM | Determine free fraction; if free concentration is ≥1 μM, then test for broad ligand activities; routinely measure in safety and clinical studies if active at a secondary receptor |
| Excreta | Any structure | >10 mg total body burden per day | Assess activity of the metabolite, determine whether it could be downstream of a reactive metabolite; ensure that species used in safety assessments generate the metabolite |