Points to Consider for Clinical Evaluation of Drug-Drug Interactions using Endogenous Biomarker — PMDA Early Consideration Summary

In Plain Language

This document considers how measurements of substances naturally present in the body—called endogenous biomarkers—may help evaluate whether an investigational drug affects the activity of drug-metabolising enzymes or transporters. It focuses particularly on plasma coproporphyrin-I (CP-I), a biomarker related to the transporters OATP1B1 and OATP1B3 in the liver. For CP-I, the document discusses a reported cutoff value of 1.25 for two ways of comparing measurements taken with and without the investigational drug. It says that collecting both measures over time is appropriate at this time, so their relationship with clinical drug-drug interactions can be evaluated further. If either or both measures exceed the cutoff, suitable physiologically based pharmacokinetic models could be used to estimate an inhibition constant and help predict transporter inhibition and design clinical interaction studies.

What This Guidance Covers

The document addresses the clinical evaluation of drug-drug interactions (DDIs) using endogenous biomarkers. It is a focused set of points to consider rather than a general account of every DDI assessment method: its main discussion is the use of plasma CP-I when evaluating inhibition of hepatic organic anion transporting polypeptide (OATP) 1B1/1B3 by an investigational drug. It also briefly addresses the use of endogenous biomarkers other than CP-I.

The document places this topic in the context of the ICH M12 Guideline, which it says presents endogenous biomarkers that are substrates for drug-metabolising enzymes and transporters as an emerging “Biomarker Approach” to clinical DDI evaluation. It notes that ICH M12 gives reported examples other than CP-I that may be applicable to DDI assessment. The document does not provide detailed, biomarker-by-biomarker recommendations for those other examples; instead, it emphasizes understanding each biomarker’s characteristics and validating the analytical method before use.

The stated focus is on use of the Biomarker Approach when assessing the potential of an investigational drug as a precipitant—that is, the drug being assessed for its potential to bring about an interaction. For CP-I, the points concern hepatic OATP1B1/1B3 inhibition. The document does not set out a complete protocol for a clinical DDI study or provide a universal decision rule for every biomarker and transporter.

Why It Matters

The document describes the Biomarker Approach as an emerging approach in ICH M12 and notes that its use has been actively studied in recent years. It also refers to discussions among clinical pharmacology experts from industry, academia, and regulatory agencies at the third Clinical Pharmacology Roundtable Conference in January 2024. Those discussions considered both advantages and challenges of using biomarkers in drug development and regulatory decision-making.

Against that background, the document’s purpose is to clarify current advantages and challenges and to facilitate smooth implementation of DDI evaluation based on the Biomarker Approach in Japan. For CP-I, it addresses how to interpret two measures of biomarker change, what information to collect, and how a result above a reported cutoff could be followed up. For other endogenous biomarkers, it highlights the need to understand their individual characteristics and to validate the analytical method, so that results are reliable. PMDA notes that the points reflect currently available knowledge and may change as new knowledge is obtained.

Key Recommendations

1. Consider CP-I alongside the ICH M12 Guideline when evaluating hepatic OATP1B1/1B3 inhibition. The document identifies plasma CP-I as an example of an endogenous biomarker for which a certain amount of scientific evidence has accumulated and whose availability has been suggested. Its points concern using CP-I to evaluate inhibition of hepatic OATP1B1/1B3 by an investigational drug, in conjunction with ICH M12.

2. Interpret the reported 1.25 cutoff in relation to both CmaxR and AUCR. The document reports a cutoff value of 1.25 for both CmaxR and AUCR based on the time course of CP-I. CmaxR is the ratio of the maximum concentration (Cmax) of CP-I in the presence and absence of the investigational drug; AUCR is the ratio of the area under the concentration-versus-time curve (AUC) of CP-I in the presence and absence of the investigational drug. The document says that, theoretically, AUCR for an endogenous biomarker does not exceed CmaxR when the time to Cmax (Tmax) is captured accurately. It therefore characterizes appropriately measured and calculated CmaxR as the more conservative metric.

3. Collect both CP-I measures over time at this time. The document says that it would be appropriate to collect both CmaxR and AUCR based on a time course of CP-I. Its stated reason is to further evaluate the relationship between clinical DDIs and changes in CP-I associated with administration of an investigational drug. This recommendation is specifically presented as appropriate “at this time,” rather than as a claim that one measure is sufficient for all future assessments.

4. Consider model-based follow-up if either or both CP-I ratios exceed the cutoff. If CmaxR and/or AUCR exceed 1.25, the in vivo inhibition constant (Ki) for OATP1B1/1B3 of the investigational drug could be estimated from appropriate precipitant and CP-I physiologically based pharmacokinetic (PBPK) models. The document says this could allow prediction of the degree of OATP1B1/1B3 inhibition by the investigational drug, which could then be used for the design of clinical DDI studies.

5. Prepare carefully before using another endogenous biomarker. When endogenous substrates are used to assess the potential of an investigational drug as a precipitant, the document says it is important to fully understand the characteristics of the individual biomarker in advance, in addition to validating the analytical method. These steps are identified as important for obtaining reliable results.

Practical Implications

Interpretation: For a team considering CP-I measurements, the document points toward planning to obtain a time course that can support calculation of both CmaxR and AUCR, rather than collecting only one of these summaries. This is consistent with its stated interest in further evaluating how clinical DDI findings relate to CP-I changes. The document’s comparison of the ratios also makes accurate capture of Tmax relevant to interpreting the theoretical relationship between them.

Interpretation: A result above 1.25 is a reason to consider the model-based follow-up described in the document; it should not be recast as a complete answer to every question about clinical interaction risk. The text says that Ki could be estimated using appropriate precipitant and CP-I PBPK models, and that the estimate could support prediction and clinical study design. It does not say that a single ratio automatically determines the outcome or design of a study.

Interpretation: Teams working with a biomarker other than CP-I should not assume that CP-I’s reported cutoff or measurement considerations transfer to that biomarker. The document instead directs attention to the characteristics of each individual biomarker and to analytical-method validation. In practice, those matters are relevant to biomarker selection and measurement planning; the document does not give a specific validation checklist or a cutoff for other biomarkers.

Technical Details

The key technical quantities in the CP-I discussion are ratios of measurements with the investigational drug present and absent. In this context, Cmax is the maximum observed concentration of CP-I, while AUC is the area under its concentration-versus-time curve. The corresponding ratios can be represented as follows:

The reported cutoff is 1.25 for each ratio. The document’s reasoning about their relationship is conditional: when Tmax is captured accurately, AUCR for an endogenous biomarker theoretically does not exceed CmaxR. On that basis, it describes appropriately measured and calculated CmaxR as the more conservative metric. The document nevertheless says that collecting both measures based on the CP-I time course would be appropriate at this time, to help evaluate their relationship with clinical DDIs and CP-I changes.

The follow-up described for results above the cutoff uses PBPK models. PBPK means physiologically based pharmacokinetic; in this document, the proposed estimation uses appropriate models for the precipitant and CP-I to estimate the investigational drug’s in vivo Ki for OATP1B1/1B3. The document presents this as a possible next step, not an automatic consequence: the estimate could be used to predict the degree of transporter inhibition and could inform the design of clinical DDI studies.

For endogenous biomarkers other than CP-I, the document’s technical point is preparatory rather than numerical. It emphasizes understanding the specific biomarker’s characteristics and validating the analytical method before applying the Biomarker Approach. It does not state a general cutoff, formula, or model-based decision rule for all other endogenous biomarkers.

Who Should Read It

This document is relevant to clinical pharmacologists, pharmacokineticists, biostatisticians, clinical operations teams, regulatory affairs professionals, and investigators involved in evaluating potential DDIs of investigational drugs. It may be especially useful when a team is considering CP-I measurements in relation to hepatic OATP1B1/1B3 inhibition, deciding which CP-I summaries to collect, or considering how a result above the reported cutoff might inform modelling and study design. It is also relevant to teams considering other endogenous biomarkers, because it draws attention to biomarker-specific characteristics and analytical-method validation.

Official PMDA Source

• Official title: Points to Consider for Clinical Evaluation of Drug-Drug Interactions using Endogenous Biomarker (Early consideration)
• Issuing body: Pharmaceuticals and Medical Devices Agency, Center for Product Evaluation
• Date printed on the cover: February 14, 2025
• English-version note printed in the document: Provisional Translation (as of September 2025)
• PMDA PDF: Official PMDA document (PDF)
• PMDA list page: PMDA Early Consideration documents

Source: Pharmaceuticals and Medical Devices Agency (PMDA) website, PMDA Early Consideration documents. This page was created by editing and summarising the PMDA document.

Consult the official document for the complete text; this summary does not replace it. PMDA provides the English version for reference, and the Japanese original prevails if the two differ. PMDA describes Early Consideration documents as reference information reflecting the Agency’s views at the time of publication, which may change as scientific knowledge develops.

Related Clinical Biostats Resources

• Cmax, Tmax and Exposure Metrics in Clinical Pharmacology explains the exposure measures used in this document’s CP-I discussion.
• All Clinical Biostats tutorials provides access to other educational summaries and tutorials.
• Statistical Calculators provides calculators for related quantitative work.