While investigating your drug's metabolic qualities, you will also want to include enzyme induction studies to highlight potential issues with achieving efficacious plasma concentrations of concomitantly administered medications when your drug induces or enhances an enzyme expression. Enzyme induction can result in increased metabolic clearance or toxicity that is caused by increased systemic exposure of active metabolites.
Induction of CYP enzymes (typically CYP1A2, CYP2B6 and CYP3A4) is measured in vitro following exposure to test article in monolayer cultures of human hepatocytes.
Initial experiments should investigate the potential to induce CYP1A2, CYP2B6, and CYP3A4 enzymes. If induction of CYP3A4 enzymes is observed, the sponsor should also evaluate the induction potential of CYP2C enzymes (CYP2C8, CYP2C9, CYP2C19). The effects are then compared with those elicited by positive control inducers of the CYP enzymes under investigation. In addition, ex vivo animal livers (typically mouse, rat, dog, or monkey) can be processed to subcellular fractions and used to assess test article mediated effects on drug metabolizing enzymes following in vivo administration during safety assessment studies.
Regulatory considerations for enzyme induction studies
These studies are recommended by both FDA and EMA drug-drug interaction (DDI) guidelines to evaluate cytochrome P450 induction for CYP1A2, CYP2B6,CYP2C8, CYP2C9, CYP2C19, and CYP3A4 before going to first-in-human trials.
Induction data is used in determining the requirement and scope of clinical DDI studies.