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ICH M12 2024 vs FDA 2020 DDI Guidance – Exploring the Differences

ICH M12 2024 vs FDA 2020 DDI Guidance. Exploring the Differences.

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The new ICH M12 guideline on drug interaction studies is welcomed by industry as it provides a harmonized approach which is expected to be implemented by the major regulatory authorities such as the US Food and Drug Administration (FDA), European Medicines Agency (EMA) and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) and presumably replace their respective existing guidance. In this blog, we explore the differences between the now finalized ICH M12 guideline adopted in May 2024 (draft for comment released 2022) and the previous US FDA 2020 guidance released in January 2020 with a focus on the in vitro assays.

Before we launch into the individual assays, one general observation in the new ICH M12 guideline is the replacement of the term ‘victim’ to ‘object’ to denote an investigational drug (usually a substrate) which is affected by a concomitant drug, and the replacement of the term ‘perpetrator’ to ‘precipitant’ to denote an investigational drug (typically an inhibitor or inducer) which affects a concomitant drug. This amendment only appeared in the final version of the ICH M12 guideline as it was one of the comments from review of the draft version.

Reaction Phenotyping

If we consider reaction phenotyping initially, the differences between the new ICH M12 and the FDA 2020 guidance are relatively minimal. Although the ICH M12 refers to all the enzymes mentioned in the FDA guidance, it also refers to some additional Phase II enzymes which may need to be evaluated including glutathione S-transferases (GSTs) and N-acetyl transferases. Both the ICH M12 and the FDA guidance have the same cut-off of ≥25% of total elimination identified using in vitro studies (reaction phenotyping and metabolite identification) and human mass balance data for determining if the enzyme needs further investigation in a clinical study. One key difference is that the FDA guidance recommends two methods should be used for reaction phenotyping – the first method using selective inhibitors in the presence of human liver microsome or hepatocytes and the second method using human recombinant enzymes. In the ICH M12 guidelines, only one of these methods is required.

Both the ICH M12 guideline and the FDA guidance have recommendations for evaluating metabolites in reaction phenotyping studies if the exposure levels of the metabolite results in clinically relevant changes in efficacy or safety.

Enzyme Inhibition

Moving onto enzyme inhibition, both the ICH M12 and FDA guidance recommend evaluating the main seven CYP isoforms for reversible and time dependent inhibition. For reversible inhibition, the cut-off for determining if a clinical study is required is the same for both the ICH M12 and FDA. However, for time dependent inhibition, 5 x Cmax,u is used in the calculation in the ICH M12 whereas a higher safety factor of 50 x Cmax,u was used in the 2020 FDA guidance, suggesting a less conservative approach is used in the new ICH M12 guideline.

One addition to the ICH M12 guideline, which is not specifically included in the previous FDA 2020 guidance, is the inclusion of reversible UGT inhibition. The ICH M12 recommends that UGT1A1, UGT1A4, UGT1A9, UGT2B7 and UGT2B15 inhibition should be evaluated if direct glucuronidation is one of the major elimination pathways of the investigational drug. Although it is considered an area of ongoing research, it is currently recommended in the ICH M12 that the same cut-off values should be used for UGT inhibition that is applied to CYP enzymes (i.e., Cmax,u/Ki,u<0.02).

Enzyme Induction

For enzyme induction, the FDA guidance suggested either catalytic activity or mRNA could be used to assess induction. It also suggested that immortalized hepatic cell lines may be used to determine CYP induction potential. However, the new ICH M12 primarily recommends the analysis of mRNA (with the exception of CYP2C19 where catalytic activity should be measured) and that the CYP induction assessment should be performed in human hepatocytes. The ICH M12 guideline also addresses the issue of toxicity and recommends that cell viability assessment is performed before and at the end of the incubation.

For data analysis, both the ICH M12 and FDA cover the three basic methods (fold-change, relative induction score correlation method and basic kinetic model) and align on the cut-offs for indicating if an investigational drug has the potential to induce in vivo. However, for the basic mRNA fold method in the ICH M12 guideline describes assessing test drug concentration of 50 x Cmax,u whereas the FDA only suggests testing up to 30 x Cmax,u suggesting a more conservative approach now by the ICH M12. Furthermore, in the calculations for the correlation methods and the basic kinetic model, unbound EC50 (EC50,u) is specified in the ICH M12 whereas only EC50 is referred to in the FDA guidance. Finally, the ICH M12 describes in more detail an indicative positive control response for CYP1A2, CYP2B6 and CYP3A4 of typically at least 6-fold to ensure sufficient sensitivity of system, whereas this level of detail is absent from FDA.

Transporter Substrate Identification

Both the ICH M12 guideline and the FDA DDI guidance (2020) recommend the same transporters are assessed. The method for testing and thresholds for clinical assessment are very similar between the FDA and ICH M12.

Transporter Inhibition

For transporter inhibition, the same transporters are recommended in the ICH M12 as the previous FDA guidance, however, the cut-off value for determining if a clinical study should be performed are different in a couple of instances. Firstly, for P-gp and BCRP inhibition where the investigative drug is administered by the parenteral route or if a metabolite is formed post absorption, the cut-off value in ICH M12 is an IC50 of 50 x Cmax,u, whereas in the FDA guidance it is 10x Cmax total; important to note the additional difference for what is defined as [I]. This indicates a more conservative approach by the FDA when plasma protein binding is > 80%, or by ICH M12 when plasma protein binding is < 79%. The second instance applies to the cut-off value for MATE1 and MATE2-K, which has increased to an IC50 of 50 x Cmax,u rather than 10x Cmax,u, indicating a more conservative approach by the ICH M12 for these renal transporters. The ICH M12 also specifically refers to unbound IC50 (IC50,u) in the calculations whereas the FDA guidance only references IC50. In this regard, it is important to recognize that any correction of IC50 for potential non-specific binding that might occur within a transporter inhibition assay would only be required if the assay did not incorporate a pre‑incubation step with investigational drug as standard methodology for all transporters prior to the co‑incubation with fresh investigational drug solution and probe substrate. With such standard methodologies, the inclusion of the pre‑incubation step would be anticipated to mask any non-specific binding sites therefore the co‑incubated concentrations of investigational drug would be nominal for IC50 fitting purposes, i.e. IC50 = IC50,u.

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