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ICH M12 Step 4: what's new in DDI studies regulation?


In May 2024, the International Council for Harmonisation (ICH) published the final version of the M12 guideline, marking a pivotal step towards standardizing drug-drug interaction (DDI) studies. The ICH M12 Step 4 guideline emphasizes the crucial role of in vitro assessments in identifying potential DDIs early in the drug development process. This brief article explores the key changes introduced in ICH M12, the growing importance of in vitro assessments, and the implications for the pharmaceutical industry.


Standardization of In Vitro Study Design

The ICH M12 guideline aims to harmonize the design and conduct of in vitro DDI studies across different regulatory regions. It introduces standardized protocols for in vitro studies, including specific test systems, concentrations, and time points. This standardization reduces variability and enhances the comparability of data, facilitating more accurate predictions of clinical DDI outcomes. By focusing on predictive models, ICH M12 enables better estimation of the clinical impact of DDIs based on in vitro data, which is critical for making informed decisions early in the drug development process.

For example, a drug undergoing oxidative metabolism may be evaluated against a panel of common CYP enzymes such as CYP1A2, CYP2C19, and CYP3A4 using in vitro phenotyping experiments. If the drug is found to be metabolized significantly by CYP3A4, further clinical DDI studies using strong inhibitors or inducers of this enzyme can be designed to quantify interaction risks.


Comprehensive In Vitro Assessments

The guideline provides detailed recommendations for conducting in vitro DDI studies, which are essential for identifying potential interactions early in the drug development process. This includes evaluations of interactions with key enzymes (such as CYP450 enzymes) and transporters (such as P-gp and BCRP). The guideline emphasizes mechanistic studies to understand the pathways involved in DDIs, improving the accuracy of in vivo predictions. Additionally, it provides guidance on evaluating the DDI potential of metabolites, which can significantly impact the pharmacokinetics of a drug.

For instance, a drug acting as a substrate for P-gp may have its absorption and bioavailability affected by other P-gp inhibitors. An in vitro study demonstrating significant P-gp-mediated transport can inform the need for clinical studies to evaluate this interaction further.


Risk-Based Approach to DDI Assessment

ICH M12 introduces a risk-based approach to DDI assessment, optimizing resource allocation and study efficiency. Compounds are prioritized based on their potential for causing clinically significant DDIs, guiding the extent of required studies. The guideline suggests strategies for mitigating identified risks, such as labeling recommendations and clinical monitoring. This approach ensures that resources are focused on the most critical areas, enhancing the overall efficiency of the drug development process.

For example, if in vitro studies indicate a high potential for a drug to inhibit CYP2D6, but the clinical relevance is uncertain, the drug can be prioritized for further clinical investigation. A risk-based approach might involve conducting a DDI study using a sensitive CYP2D6 substrate to confirm the interaction and determine appropriate management strategies.


No Requirement for Animal Validation

According to the ICH M12 guideline, validation of drug induction and inhibition does not need to be performed on animals. The guideline emphasizes in vitro and clinical studies for evaluating drug interactions. In vitro studies are critical for identifying potential interactions early in drug development, and these findings guide further clinical studies to confirm the interactions and determine their clinical significance. The focus is on human-based test systems to ensure relevance and accuracy in predicting human drug interactions.


LC/MS-MS and PCR in Induction Studies

The ICH M12 guideline does not mandate the use of LC/MS-MS for induction studies, although it remains a valuable tool. LC/MS-MS is commonly used to quantify changes in enzyme activity and metabolite levels, providing comprehensive data on drug metabolism. However, PCR , particularly quantitative PCR, is also sufficient for assessing the induction potential by measuring changes in mRNA levels of target enzymes.


Alignment with EMA and FDA Guidelines

The ICH M12 guideline aligns with existing guidelines from the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA), but with notable enhancements. EMA guidelines have traditionally emphasized the need for clinical confirmation of in vitro findings, whereas ICH M12 promotes a more integrated approach, ensuring comprehensive enzyme and transporter assessments. The FDA has been proactive in encouraging quantitative predictions of DDIs using in vitro data and advanced modeling techniques, a principle that is strongly reflected in ICH M12. This harmonization facilitates global drug development and regulatory approval processes.

For example, while EMA guidelines might recommend clinical confirmation of CYP3A4 interactions identified in vitro, ICH M12 allows for the use of advanced PBPK modeling to predict in vivo outcomes more accurately, potentially reducing the need for extensive clinical trials.


The ICH M12 Step 4 guideline represents a significant advancement in the harmonization of DDI study guidelines, with a particular emphasis on the importance of in vitro assessments. By standardizing methodologies and adopting a risk-based approach, ICH M12 aims to streamline the drug development process while ensuring patient safety. For pharmaceutical companies, staying updated with the latest guidelines and effectively implementing in vitro assessments can enhance the predictability of DDI outcomes and improve overall development efficiency.


At Preci, we provide state-of-the-art in vitro models that align with the latest ICH M12 guidelines, ensuring accurate and reliable DDI assessments. Contact us today to learn more about our innovative solutions and how we can support your drug development efforts.

 

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