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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 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.

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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

In the ever-evolving landscape of biomedical research, proteomics has emerged as a crucial field for advancing drug discovery and development and biomarker discovery. Evotec stands at the forefront of this scientific frontier, offering cutting-edge mass spectrometry-based proteomics solutions. Here’s how Evotec’s innovative technologies and comprehensive services deliver exceptional value to customers, driving breakthroughs in clinical research, such as discovery of stratification biomarkers and diagnostic markers for the discovery of novel targets.

Revolutionizing Proteomics with Advanced Platforms

ScreenPep™ Platform: Evotec’s ScreenPep™ platform is a high-throughput, automated system designed for deep-coverage proteomics of cell lines, tissues or biofluids. When applied to plasma or serum it can identify up to 1,500 proteins , making it incredibly efficient and cost-effective. This platform is ideal for large-scale studies, in which sample quantity may be limited but extensive protein identification is required.

Proteograph™ Technology: As the only Center of Excellence in Europe offering Proteograph™ technology, Evotec provides an unparalleled capability to identify up to 5,000 proteins from human biofluids such as serum, plasma, and cerebrospinal fluid (CSF). This technology leverages nanoparticle-based methods to achieve deep proteome coverage, significantly enhancing the scope of biomarker discovery and translational research.

Integrated MultiOmics Solutions: Evotec excels in integrating proteomics data with genomics, transcriptomics, and metabolomics, offering a holistic approach to biomarker discovery. This integrated solution, facilitated by Evotec’s PanHunter platform, allows for comprehensive data analysis and interpretation, enabling researchers to uncover complex biological insights and accelerate drug development processes.

Customized and Scalable Services: Understanding that each research project has unique requirements, Evotec offers highly customized services tailored to meet specific client needs. From optimizing study designs to adapting sample preparation workflows for difficult and rare samples, Evotec ensures that every project receives the precise attention and expertise it demands.

Exceptional Expertise and Infrastructure: With over 20 years of experience and more than 50 mass spectrometers across its sites, Evotec is one of the largest providers of proteomics services worldwide. Their dedicated team of bioinformaticians and proteomics experts continuously develops and refines in-house pipelines, ensuring the highest standards in data quality and analysis.

High-End Mass Spectrometry: Utilizing cutting-edge mass spectrometry instruments, Evotec guarantees high-sensitivity and high-precision proteomics. These advanced technologies are crucial for detecting low-abundance proteins and analyzing post-translational modifications, providing deeper insights into protein functions and interactions.

Advantages of Mass Spectrometry-Based Proteomics

Unbiased Protein Measurement: Unlike antibody or aptamer-based techniques, mass spectrometry provides an unbiased measurement of all proteins containing tryptic peptides. This comprehensive approach allows for a more accurate and complete proteome analysis, essential for discovering new biomarkers and therapeutic targets. The quantification is also not impacted by any conformational changes.

Versatility Across Species: Evotec’s proteomics solutions are not limited to human samples; they are also applicable to various species, including animals used in health studies. This versatility broadens the research applications and facilitates translational research from preclinical models to clinical settings.

Detection of Protein Isoforms and Modifications: Mass spectrometry is uniquely capable of detecting protein isoforms and post-translational modifications, such as phosphorylation and ubiquitination. This capability is vital for understanding protein functions and regulatory mechanisms, paving the way for novel therapeutic strategies.

Cutting-Edge Technology and Continuous Innovation: Evotec’s commitment to innovation is exemplified by their continuous development of nanoparticle-based proteomics in collaboration with Seer Inc. This ongoing enhancement ensures that Evotec remains at the forefront of proteomics research, providing customers with the most advanced and reliable technologies available.

Conclusion

Evotec’s clinical proteomics capabilities offer a robust, scalable, and precise solution for drug development and biomarker discovery. By leveraging advanced technologies, integrated MultiOmics approaches, and customized services, Evotec empowers researchers to make significant scientific advancements. Partner with Evotec to unlock new possibilities in your research and drive the future of healthcare innovation.

For more information, please contact us at info@evotec.com or visit our website at PanOmics - Technology Platforms - Evotec Website (English)

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As the world increasingly turns its focus toward sustainability, the pharmaceutical industry is not exempt from this shift. One company leading the charge is Evotec, a global drug discovery and development biotech who offer CRO and CDMO services. Evotec’s commitment to green chemistry is setting new standards for sustainability in medicinal chemistry, particularly in how drug discovery processes are designed and executed. This blog post will delve into Evotec’s green chemistry initiatives and how they are revolutionizing the pharmaceutical industry.

Evotec’s Commitment to Green Chemistry

Evotec’s green chemistry philosophy centres around minimizing the environmental impact of their chemical processes while maintaining excellence in drug discovery. This commitment is evident in their comprehensive strategy that encompasses various innovative approaches and technologies designed to make their operations more sustainable.

Key Initiatives in Green Chemistry

1. Safer Solvents and Reduced Plastic Waste
   • Evotec prioritizes the use of safer solvents, particularly those sourced from renewable bio-based origins, to reduce the reliance on chlorinated solvents known for their environmental and health hazards.
   • They actively work on reducing plastic waste by encouraging the reuse and recycling of plastic consumables in their laboratories.
2. Energy Efficiency
   • Energy conservation is a significant aspect of Evotec’s sustainability efforts. Simple yet effective practices like shutting laboratory fume cupboards when not in use help in reducing unnecessary energy consumption.
3. Raising Awareness and Continuous Improvement
   • Evotec fosters a culture of sustainability by raising awareness among their scientists about green chemistry alternatives through communication and poster sessions.
   • Continuous improvement of chemical processes with a sustainable vision is a cornerstone of their green chemistry initiatives.

Advanced Green Chemistry Techniques

Evotec employs several advanced green chemistry techniques that underscore their innovative approach to sustainable drug discovery:

1. Micellar Chemistry
   • Utilizing micellar properties for chemical reactions offers a new paradigm in sustainable chemistry, reducing the need for harmful organic solvents.
2. Mechanochemistry
   • This technique uses mechanical forces to drive chemical reactions, which can be more sustainable than traditional methods reliant on solvents and reagents.
3. Flow Chemistry
   • Flow chemistry enhances productivity and safety, offering better control over reaction conditions and significantly reducing organic waste.
4. Biocatalysis
   • By employing enzymatic processes, Evotec can replace traditional organic synthesis routes, reducing the use of toxic reagents and conditions, whilst often also increasing yields.

Practical Applications and Case Studies

Evotec has documented numerous case studies showcasing the practical application of green chemistry in their labs. These include:

1. Solvent Replacement
   • Evotec has successfully replaced conventional hazardous solvents like DMF, DCM, and THF with greener alternatives such as Me-THF, CPME and dimethyl isosorbide (DMI), achieving comparable or superior yields in various reactions while reducing toxicity and environmental impact.
2. Catalyst Optimization
   • By optimizing catalyst loading in reactions, such as pallado-catalyzed cross-couplings, the company has significantly reduced the amount of precious metals required, decreasing both environmental impact and costs.
3. Sustainable Work-Up Methods
   • The adoption of FastWoRX™, a technique that significantly reduces the amount of solvent used in the work-up phase, demonstrates Evotec’s commitment to minimizing waste.
4. Better purification processes
   • Rethinking our working habits in a smarter and sustainable way. Avoid systematic normal phase flash column chromatography (or reuse, if necessary). Favour reverse phase and crystallization/recrystallization.

The Future of Green Chemistry at Evotec

Evotec’s approach to green chemistry is not static; it is an evolving process that aims to continually integrate new technologies and methodologies. The company's dedication to sustainability is reflected in their global initiatives and partnerships, fostering a greener pharmaceutical industry.

In conclusion, Evotec is at the forefront of green chemistry in drug discovery. Their innovative approaches and commitment to sustainability set a benchmark for the industry, proving that excellence in drug discovery and environmental stewardship can go hand in hand. As Evotec continues to develop and implement green chemistry practices, they pave the way for a more sustainable future in medicinal chemistry.

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In the quest to revolutionize immunotherapy, the identification of naturally presented peptides bound to HLA class I and II molecules from cancerous cells holds paramount importance. These peptides, crucial for developing immunotherapy-based treatments, also offer promising avenues for combating infectious diseases. Evotec's pioneering immunopeptidomics platform stands at the forefront, enabling the unbiased discovery of novel immunotherapeutic targets.

This comprehensive approach extends beyond cancer research, facilitating the identification of diagnostic and monitoring biomarker signatures across normal and altered cells in cohort studies. It sheds light on the intricate interplay between T cells and MHC-presenting cells, deepening our understanding of immunobiology.

Evotec's meticulously crafted experimental strategy, coupled with its state-of-the-art capabilities in high-end quantitative mass spectrometry, achieves unparalleled sensitivity. This precision is essential for distinguishing disease-specific neoantigens from their normally presented counterparts. By integrating whole exome sequencing and transcriptomics data, the platform empowers the discovery of neoepitopes, while advanced statistics and bioinformatics tools enable comprehensive data analysis and interpretation, facilitating peptide prioritization.

The platform's capabilities are exemplified by its ability to identify up to a thousand peptides per sample, providing direct detection of presented peptides, surpassing computation-intensive in silico predictions. Moreover, validation and accurate quantification of individual peptides are ensured through targeted mass spectrometry (PRM-MS).

In essence, Evotec's immunopeptidomics platform represents a transformative leap in the field, offering unparalleled insights into immunobiology and neoantigen identification, with profound implications for the development of immunotherapy-based treatments and the fight against various diseases.

For further inquiries, contact Evotec's experts at info@evotec.com or learn more here 

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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