Welcoming the new harmonized ICH M12 guideline for drug interaction studies

Posted on June 6, 2024

On May 21st 2024, the International Council for Harmonization (ICH) published the final guideline for drug interaction studies (ICH Harmonised guideline – Drug interaction studies M12). It guides how and when to investigate new drug candidates regarding the drug – drug interaction (DDI) risks, either as a drug whose PK properties are affected by another drug (previously referred to as ”the victim”, now phrased as “the object”), or as a drug that causes changes to PK of another co-medicated drug (previously “the perpetrator”, now “the precipitant”). The guidance describes broad requirements regarding in vitro and clinical studies used to evaluate if the compound, or in some cases a metabolite, is a substrate, inhibitor or inducer of various drug metabolizing enzymes (e.g. CYPs or UGTs) or intestinal, hepatic or renal transporters that actively affect the pharmacokinetics of either the investigated compound or co-medicated drugs. All of these together have a major effect when evaluating concerns regarding the safety and efficacy of the investigated compound, and the information should be available before proceeding any further in clinical development with the new compound.

Historically, regulatory agencies from different geographical areas, e.g. European Union (EMA), United States (FDA) and Japan (PDMA ) have had their own guidelines for this purpose, containing mostly similar, but also partially different recommendations how to investigate the DDI potential of new compounds. The first attempt to harmonize these various guidelines was the ICH M12 draft version published in 2022, which is thus now recently updated and finalized. The purpose of the harmonization has been to avoid challenges in regulatory clearance between different geographical areas, decreasing the need for region specific guidelines and studies, and to confirm similar requirements for safety and efficacy for pharmaceuticals globally.

The new and final M12 guideline generally follows the same instructions and principles that were set up in the earlier draft version, but there are some differences to consider. Perhaps the most interesting is the statement that emerging modalities such as oligonucleotides and peptides are out of scope for the M12 guideline. It will remain interesting to see, if this will be interpreted so that IND stage DDI experiments, which in the lack of clinically relevant related DDI examples are often considered as “check-box studies”, are not needed anymore for these modalities, whose relative number in development pipelines are ever-increasing.

Other interesting items to mention; the final guideline clearly highlights the importance of using unbound test and plasma concentrations when evaluating the risk for inhibition or induction of metabolizing enzymes and transporters, a topic which was previously was not aligned between FDA and EMA recommendations. Related to this, the final guideline also comments that in the development of methodologies used to evaluate unbound fractions, values below 0.01 (i.e. 1%) could be used in the risk assessment, on the contrary to the draft guideline that recommended to use this threshold value (0.01 / 1%) for highly protein bound drugs. The new guidance also gives requirements for assay validation and analytical performance for evaluation of these very low unbound fractions. As this may lead to lower unbound Cmax-values, the less conservative approach may decrease the predicted interaction risk for highly bound compounds. However, at the same time, the final guideline also recommends to use concentrations of 50 × Cmax,u for evaluation of CYP induction risk, while the earlier draft stated 15 × Cmax,u. One more detail related to evaluation of CYP inhibition potential is that based on the new guideline, both dilution and non-dilution methods can be used for the IC50 shift assay, while the draft version recommended the dilution assay only.

While this new guidance, similarly to the earlier versions, does focus on comprehensive investigations during the late stage of preclinical development, it is worth noting that the implementation of related screening procedures in the earlier stages of the preclinical project is the key to a successful late-stage compound with minimized DDI risks. Therefore, fit for purpose screening assays for hit-to-lead and lead optimization stages are crucial, to decrease potential for acting as precipitant of DDIs, and early understanding of metabolizing enzymes and transporters involved in clearance and pharmacokinetics of the compounds increases changes for successful prediction of human pharmacokinetics from in vitro assays and animal studies. As the preclinical project advances, all gathered information can be used to design the next steps in research, increasing the level of complexity and performance of the experiments. The Admescope team is very experienced in planning and designing the right studies for each stage, and we are happy to help you with early screenings and tailor-made studies.

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