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Is your Drug-Drug Interactions package up to date with ICH guidelines?

Last June , the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) published a harmonized draft drug-drug interaction (DDI) guideline (ICH M12), providing recommendations for in vitro and in vivo DDI studies for new medicinal products (read more about DDIs in this blog post). After being made available for public consultation globally until November 2022, the document is now being reviewed and potentially updated. The guideline is generally relevant to small molecule drugs, but some consideration is also given to therapeutic proteins and antibody-drug conjugates (ADCs). The document is not as comprehensive as some of the regional guidelines, such as the EU one, which also considers food effects, DDIs with herbal medicines and absorption-related DDIs including pH-mediated ones. Thus, regional guideline(s) remain valid and will still need to be consulted for topics such as the aforementioned ones.

The ICH M12 remains a draft guideline. Although it reflects the current regulatory thinking, it is not likely to be enforced or fully implemented until its finalisation and adoption by regional agencies, which is likely to occur in 2024. Despite this, the ICH M12 indicates how the data-driven requirements for in vitro and in vivo DDI studies are likely to change and as such should be used as a reference point from here on, especially as there are likely to be minimal changes to the guideline during the revision process.  

Time to review and update your DDI packages!

We recommend a review of all available in vitro (and in vivo) DDI data with “fresh eyes” and perspective.

  • Do your in vitro studies fulfil the requirements of the ICH M12 guideline?
  • After implementation of the ICH M12 guideline, will a negative DDI risk remain so or be considered positive or inconclusive? Or will your planned in vivo DDI study no longer be required as your assumed positive in vitro signal is now considered negative?
  • Are the upcoming changes already factored into your program timelines, or could the program be put on hold next year due to lack of relevant in vitro data?

For some scenarios, the draft guideline has less strict criteria (cutoffs, R-values) i.e. for when an in vitro signal is considered to be relevant in vivo. For example, a positive in vitro signal previously identified for a time-dependent-inhibitor (TDI) may now lose its in vivo relevance. However, the requirements for in vitro studies may have intensified; for example, % recoveries which reflect the reliability of the study. Thus, take a closer look at the draft ICH M12 DDI guideline to determine whether your in vitro data or planned studies will reach the desired standard!

Proposed changes in the ICH guideline

The DDI guideline is detailed. Hence, we have provided an overview of the key changes below and a summary in the table for quick reference.

Timing: The availability of data to inform DDI decision making during development is key. Timing is of the essence! Whilst generation of in vitro metabolism data including reaction phenotyping, assessment of perpetrator effect, and conduct of the mass balance study remains as before, DDI assessment of metabolites can now be conducted downstream in drug development.

Risk assessment: In the “in vitro” section of the guideline, less strict criteria may be used to indicate when a perpetrator signal is positive. The “cutoffs” are to a significant extent, data driven and based on current knowledge. The expectation is that they will be informed by high quality in vitro data. Hence, recommendations on in vitro study design and data interpretation are discussed in detail in the guideline.

Table: Summary of key changes in ICH M12 guideline

In vitro studies
Topic/InvestigationNew in draft ICH M12
General Principles (Timing)
  • In vitro reaction phenotyping (enzymes) generally before Phase 1 (as previously)
  • In vitro perpetrator effects on CYP and transporter generally before administration to patients
  • In vitro interactions for major/active metabolites may be later in development
Substrate of Metabolizing Enzymes
  • List of 11 UGTs to screen if the drug is mainly eliminated by direct glucuronidation
  • N-acetyltransferases and glutathione S-transferases added as “other Phase 2 enzymes” list
CYP Reversible Inhibition
  • In some situations, the measured drug free fraction in plasma can be used to estimate the risk with the basic method for highly bound drug (≥99.9%)
CYP450 Time-dependent Inhibition (TDI)
  • Less stringent basic static risk assessment
  • Turnover rate constant (Kdeg) of major CYPs is now specified
UGT Inhibition
  • Perform if the drug is mainly eliminated by direct glucuronidation or is to be used with another drug that is mainly glucuronidated
CYP Induction
  • CYP2C19 via enzyme activity (not mRNA)
  • Less stringent basic fold-change risk assessment
  • Use actual (not nominal) unbound drug concentration
  • Positive controls should have at least ≥6-fold mRNA increase
  • RIS (Relative Induction Score) correlation method can be done with only 1 qualified batch of hepatocytes
Substrate of Transporters
  • Additional transporters (MRP2, OATP2B1, OCT1) on a case-by-case basis
  • Evaluate if a drug is a substrate of OATP1B1 and OATP1B3 when the pharmacological target is in the liver
  • Evaluate if a drug is a substrate of renal transporters when the drug has renal toxicity
Transporter Inhibition
  • Additional transporters (BSEP, MRP2, OATP2B1, OCT1) on a case-by-case basis
  • Harmonization of cut-off values between FDA and EMA
  • Equation for drug administered parenterally that inhibits P-gp or BCRP
DDI of Metabolites
  • Metabolite as a substrate if it contributes to in vivo target effect to a similar or greater extent than the parent drug
  • Metabolite as inhibitor (CYP and transporters) if ≥ 25% of AUCparent and ≥10% of drug-related material in circulation
  • Induction study of metabolite if 1) drug is a prodrug or 2) metabolite mainly formed extra-hepatically
Assay Conditions
  • Detailed guidance to ensure drug solubility, lack of cytotoxicity, and adequate recoveries/stability in assays
In vivo studies
General Principles (Timing) 
  • The human absorption, metabolism, and excretion study (hAME) results should generally be available before Phase 3 (read more about hAME studies in this blog).
  • Based on the results, in vivo victim DDI studies are planned and if required, further in vitro metabolism and transport studies identified.
In vivo studies
  • If the DDI effect is changing over time (I.e., combined inhibitor and inducer) – evaluate the DDI early and late during co-treatment.
  • In general, there are no new requirements but more extensive information on study design, considerations for choosing index drugs for DDI studies, etc. is required.

In conclusion, although the ICH M12 guideline is a draft, you should plan for its finalization and implementation. Are your DDI data ready for prime time?

If you’d like to read more of our thoughts on regulatory expectations and modeling & simulation approaches for assessing DDIs for therapeutic proteins, please read this white paper.

About the authors

Eva Gil Berglund, PhD
By: Eva Gil Berglund, PhD

Eva is a pharmacist by training and has a PhD in Clinical Pharmacology, both from Uppsala University, Sweden. She has been a Clinical Pharmacology reviewer at the Swedish Medical Products Agency for over 20 years and a Senior Expert for 12 years, working with all types of molecules in marketing applications, clinical trials and scientific advice procedures in the EMA Network of National agencies. Eva joined Certara in 2019 and provides her Clinical Pharmacology experience and Regulatory strategy knowledge in GAP analyses, regulatory stress tests and mock meetings, regulatory interactions, filing and clin pharm response support, pediatric submissions (PIP, PSP, new indications).

Nathalie Rioux
By: Nathalie Rioux

Dr. Rioux joined Certara in October 2018 and is now a Vice President of Integrated Drug Development. Nathalie obtained her Ph.D. in Pharmacy at Laval University, Quebec, Canada, where she studied lung cancer chemoprevention by non-steroidal anti-inflammatory drugs and lipoxygenase inhibitors.  Following graduate school, Nathalie completed an industrial post-doctoral fellowship in drug metabolism, sponsored by NSERC Canada/Biochem Pharma. 

Nathalie has more than 15 years of experience in the pharmaceutical industry, in biotech, pharma, and CRO service.  After being a DMPK lab head & project leader for multiple antiviral drug development projects at Boehringher Ingelheim Canada, she moved to a principal scientist role at Epizyme, where she represented DMPK on multidisciplinary oncology discovery and nonclinical programs including alliances with GSK, Eisai, and Celgene.  Most recently, she built the DMPK, bioanalytical and clinical pharmacology group at H3 Biomedicine in Cambridge, MA, where she drove the strategic and tactical activities around ADME, PK/TK, bioanalysis, and modeling across the discovery and development space.  At H3, she acted as a member of the development leadership team, where she contributed to regular review of project strategy, selection of development candidate, and multiple due-diligence activities.  Nathalie has co-authored multiple regulatory documents and contributed to several development compounds in H3’s Phase 1/1b oncology program. 

Karen Rowland Yeo, PhD
By: Karen Rowland Yeo, PhD

Since 2002, Karen has led projects relating to the extrapolation of in vitro data to predict in vivo pharmacokinetics in humans. This has included development and implementation of the models into the Simcyp Simulator.  Her specific research interests include physiologically based pharmacokinetic modeling and prediction of drug-drug interactions.