The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) adopted a harmonized drug-drug interaction (DDI) guidance (ICH M12) in May 2024. The next step is for this guidance to be implemented by ICH members; the FDA and EMA have already implemented the guidance.

Prior to implementation of this harmonized guidance, DDI guidances have differed between the FDA in the US, EMA in the EU, and the PMDA in Japan, which resulted in different recommendations for DDI studies in these regions. The M12 guidance provides a consistent approach to the design, conduct, and interpretation of in vitro and in vivo DDI studies, aimed at reducing uncertainty for sponsors to meet the requirements of different regulatory agencies. The focus of ICH M12 is pharmacokinetic drug interactions, which are generally applicable to small molecules, although there is discussion of DDI evaluation for monoclonal antibodies and antibody-drug conjugates. Oligonucleotides, siRNA, and peptides are out of scope for this guidance. For any interactions not covered by ICH M12, such as food effects, protein binding displacement, and interactions that may affect absorption, regional specific guidances should be followed.

Key highlights of the 2024 ICH M12 Guidance include:

• Clarified nomenclature: instead of “perpetrator” and “victim” nomenclature, drugs that cause interactions with other drugs are described as “precipitants” and drugs that are subject to interactions are described as “objects”
• For in vitro evaluations of investigational drugs that are metabolism substrates, the guidance lists 11 UGT enzymes to be evaluated in vitro and adds Phase 2 enzymes N-acetyl transferase and glutathione S-transferase to the list of other enzymes to be evaluated if non-CYP-mediated metabolism is suspected
• Recommendations for drug interaction evaluations for substrates and inhibitors of UGT enzymes:
  • If direct glucuronidation is a major elimination pathway of an investigational drug, in vitro evaluations of whether the drug can reversibly inhibit UGT are recommended
  • For investigational drugs that are mainly eliminated by direct glucuronidation or are potential UGT inhibitors, clinical DDI studies should be conducted on a case-by-case basis, considering the likelihood of concomitant use with UGT inhibitors (for objects) or substrates (for precipitants)
• Information on use of the change in exposure of endogenous biomarkers such as coproporphyrin I (hepatic OATP1B1/3), plasma 4β-hydroxycholesterol/cholesterol ratio or urine 6β-hydroxycortisol/cortisol ratio for CYP3A, plasma pyridoxic acid (renal OAT1/3), or plasma and urine N1-methylnicotinamide and N1-methyladenosine (renal OCT2, MATE1, MATE2K) to evaluate the potential of an investigational drug to be a precipitant of an interaction
• Harmonization of in vitro R value calculations used to evaluate the potential for clinical drug interactions
• Updates on recommendations for protein binding measurements for highly bound drugs

The harmonized guidance includes many additional details, and we recommend that sponsors review their in vitro and in vivo DDI studies to ensure their DDI assessments align with the new 2024 ICH M12 harmonized DDI guidance. It is highly recommended to perform risk assessments for both prevention and risk minimization of drug interactions, and Rho can help support such risk assessments. Our nonclinical and clinical pharmacology experts at Rho can help you evaluate and ascertain next steps for your DDI program in light of this new guidance. Contact us for more information.

Amanda Mathis, PhD, Director, Clinical Pharmacology, has more than 17 years of experience in the pharmaceutical industry, with more than 12 years experience as a clinical pharmacologist. Prior to joining Rho, she led clinical pharmacology efforts at small and mid-sized pharma and biotech companies, developing the clinical pharmacology strategy for multiple clinical development programs within diverse therapeutic areas. Dr. Mathis has supported multiple IND and NDA submissions and has extensive experience authoring clinical protocols, study reports, regulatory submissions modules, briefing packages for regulatory meetings, and other regulatory documents.