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Download this fact sheet to learn more about the PXR, AhR and CAR3 nuclear receptor activation assay including:

• Background information
• Assay details 
• Data generated in the nuclear receptor activation assay
• The benefits of using Cyprotex

Download this fact sheet to learn more about how Cyprotex can support you in the design and implementation of high throughput ADME and physicochemical profiling studies.

We offer a rapid flexible service delivering high quality data for a comprehensive range of assays to support your drug discovery project.

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Download this fact sheet to learn more about how Cyprotex can support you in assessing the clearance of your test article using our microsomal stability assay.

Through the use of liquid handling automation and high resolution mass spectrometry, high quality data is delivered rapidly to feed into drug discovery programs.

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The long-awaited ICH M12 harmonised guideline on drug interaction studies was adopted on 21^st May 2024. It is just a matter of time before it is implemented by the main regulatory agencies – in fact, the European Medicines Agency has already reached Step 5 of the process and announced that the guideline will come into effect on 30^th November 2024. Therefore, it is essential companies are prepared for the change and know how the ICH M12 guideline differs from earlier guidance/guidelines so data can be collected and analysed correctly according to the new recommendations.

Cyprotex has produced some easy-to-follow flyers which highlight the key differences between existing guidance/guidelines from the US FDA, European Medicines Agency (EMA) and Japanese PMDA and the new harmonised ICH M12 guideline. These will help you get started on the transition process.

US FDA vs ICH M12 Flyer

European Medicines Agency (EMA) vs ICH M12 Flyer

Japanese PMDA vs ICH M12 Flyer

Cyprotex is a centre of excellence for drug-drug interaction (DDI) studies. Our highly experienced team provide consultancy and guidance, and support you with the design, implementation and interpretation of in vitro DDI studies according to the regulatory guidance/guidelines, including the new ICH M12 guideline.

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DOWNLOAD OUR HANDY COMPARISON SUMMARY

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 C_max,u is used in the calculation in the ICH M12 whereas 50x C_max,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.

DOWNLOAD OUR COMPARISON SUMMARY

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Read about the newly adopted harmonized drug interaction guideline including:

• An overview of the key highlights of the new ICH M12 harmonized guideline on drug interaction studies (2024)
• A comparison with the Japanese PMDA guideline on drug interaction for drug development (2018)

LEARN MORE

DOWNLOAD OUR HANDY COMPARISON SUMMARY

The new ICH M12 guideline on drug interaction studies provides a harmonised approach which is expected to be implemented by the major regulatory authorities including the European Medicines Agency (EMA), the US Food and Drug Administration (FDA), and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), and presumably replace their respective existing guidelines/guidance. In this blog, we explore the differences between the new ICH M12 guideline adopted in 2024 and the previous EMA guideline which came into effect in 2013. You may also be interested in our blog comparing the US FDA 2020 guidance to the ICH M12 2024 harmonised guideline (LEARN MORE). Our comparison of the Japanese PMDA 2018 guideline with the ICH M12 guideline will follow shortly.

Reaction Phenotyping

The new M12 ICH and the EMA guidelines are similar in terms of their recommendations. Both the ICH M12 and the EMA guideline have the same cut-off of ≥25% of total elimination for determining if the enzyme needs further investigation in a clinical study.

Enzyme Inhibition

For enzyme inhibition, both the ICH M12 and EMA 2013 guidelines recommend evaluating the main seven CYP isoforms for enzyme 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 C_max is used in the calculation in the ICH M12 whereas 1x C_max was used in the EMA 2013 guideline, suggesting a more conservative approach is now being used in the new ICH M12 guidance. Furthermore, in the ICH M12, only a single cut-off is provided for time dependent inhibition whereas the EMA has cut-offs for intestinal enzymes for orally administered drugs as well as systemic enzymes. The EMA currently suggest drug interactions in the GI tract will be addressed with accompanying EMA documentation.

Both guidelines suggest evaluating UGT inhibition if one of the major elimination pathways of the investigational drug is direct glucuronidation, however, the ICH M12 references a larger panel of UGT isoforms including UGT1A1, UGT1A4, UGT1A9, UGT2B7 and UGT2B15 whereas the EMA 2013 references only UGT1A1 and UGT2B7.

Enzyme Induction

The ICH M12 and the EMA 2013 guidelines are similar in terms of CYP induction. The cut-offs for the basic fold-change method and the relative induction score (RIS) are the same. For the correlation method, the ICH M12 guideline gives better clarity on the cut-off value to be used compared to the EMA guideline. The ICH M12 provides clearer guidance on how to interpret the basic kinetic model whereas the EMA 2013 guideline incorporates the model into a mechanistic static equation.

Transporter Substrate Identification

Both guidelines recommend the same transporters are assessed. The method for testing and cut-offs for clinical assessment are very similar between the ICH M12 and EMA guidelines. However, once again the ICH M12 provides more clarity on interpretation of the results especially in the case of the uptake transporters.

Transporter Inhibition

For transporter inhibition, the EMA 2013 guideline recommends screening for OCT1 and BSEP inhibition in addition to the standard transporters recommended by the ICH M12. Although these transporters are not in the standard list for the ICH M12 guideline, it is suggested they may be assessed on a case-by-case basis with other transporters such as OATP2B1 and MRP2. The cut-off values also differ between the two guidelines with the EMA 2013 guideline tending to be more conservative for certain transporters. One final difference is that the ICH M12 recommend a pre-incubation with test article for transporters such as OATP1B1 and OATP1B3 whereas the EMA 2013 guideline does not refer to a pre-incubation as the scientific literature and consensus concerning this topic only started to appear later around 2017.

DOWNLOAD OUR COMPARISON SUMMARY

Get in touch

Read about the newly adopted harmonized drug interaction guideline including:

• An overview of the key highlights of the new ICH M12 harmonized guideline on drug interaction studies (2024)
• A comparison with the EMA guideline on the investigation of drug interactions (2013)

LEARN MORE

The new ICH M12 guideline on drug interaction studies provides a harmonized approach 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.

Explore the differences between the 2020 FDA Guidance and the 2024 ICH M12 Guideline with our handy reference document.

LEARN MORE

Watch our webinar by expert Rob Elsby on assessing transporter risk during drug discovery and development.

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