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The new ICH M12 guideline harmonises drug interaction guidance from the major regulatory authorities. It is expected that the ICH M12 guideline will be implemented by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) and presumably replace their existing guidelines/guidance. In this blog, we explore the differences in the in vitro studies between the new ICH M12 guideline adopted in May 2024 and the Japanese PMDA guideline from 2018. You may also be interested in our blogs comparing with the US FDA 2020 guidance (LEARN MORE), and the EMA 2013 guideline (LEARN MORE) to the ICH M12 guideline.
Reaction Phenotyping
The new ICH M12 and the PMDA guidelines are similar in terms of their recommendations. Both have the same cut-off of ≥25% of total elimination for determining if the enzyme needs further investigation in a clinical study. The ICH M12 suggest investigating a larger range of phase II enzymes if the investigational drug is not metabolised by the main CYP enzymes whereas the Japanese PMDA only specifically name UGT enzymes for phase II.
Enzyme Inhibition
For enzyme inhibition, both the ICH M12 and PMDA guidelines recommend evaluating the main seven CYP isoforms for enzyme inhibition as well as UGT inhibition if one of the major elimination pathways of the investigational drug is direct glucuronidation. However, the ICH M12 suggests evaluating a larger panel of UGT isoforms (UGT1A1, UGT1A4, UGT1A9, UGT2B7 and UGT2B15) compared to the PMDA guideline which suggests only UGT1A1 and UGT2B7 inhibition.
For reversible inhibition, the cut-off for determining if a clinical study is required is the same in both guidelines using the basic model. However, for time dependent inhibition, 5x Cmax,u is used in the calculation in the ICH M12 whereas 50x Cmax,u was used in the 2018 PMDA guideline, suggesting a less conservative approach is now being used in the new ICH M12 guideline. Interestingly, the PMDA guideline also recommended a different cut-off for CYP3A in the GI tract for time dependent inhibition – this is not covered in the new ICH M12 guideline.
Enzyme Induction
The ICH M12 and the PMDA guidelines are similar in terms of CYP induction. The equation for the relative induction score is the same in both guidelines. Similarly, the basic kinetic model cut-offs are the same for both the ICH M12 and PMDA guidelines.
Transporter Substrate Identification
Both guidelines recommend that the same transporters are assessed. The method for testing and cut-offs for clinical assessment are very similar between the PMDA and ICH M12 guidelines.
Transporter Inhibition
For transporter inhibition, the ICH M12 and PMDA guidelines are the same in terms of the cut-offs. The only omission from the PMDA is that it only considers the oral route for P-gp and BCRP inhibition whereas the ICH M12 also considers the parenteral route for these transporters.