Regulatory Guidance for Drug Interaction Studies
SOLVO Transporter Studies for Regulatory Submission
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Did you know? In June 2022, the ICH released their M12 harmonized draft guideline on Drug Interaction Studies. The ICH, International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use, aims to harmonize guidelines released by multiple regulatory agencies for the same purpose in order to create a single reference document that can be applied across borders. The ICH M12 will ultimately become the standard guidance for Sponsors developing compounds from pre-clinical through final submission for registration. The guideline covers both in vitro and clinical drug metabolizing enzyme- and transporter-mediated drug-drug interactions by providing recommendations to support investigations and data interpretation. We are currently compiling the changes in the ICH M12 guidelines compared to existing guidance documents from various agencies. In the meantime, we invite you to browse the ICH guidelines here. |
The regulatory landscape for transporter-drug interactions has undergone a dramatic shift over recent years, with multiple revisions to relevant guidance documents released by US Food and Drug Administration (FDA), European Medicines Agency (EMA), and Japanese Pharmaceuticals and Medical Devices Agency (PMDA). With over 20 years’ focused experience on drug transporters, and the broadest array of transporter products and services available on the market, SOLVO Biotechnology has partnered with hundreds of companies world-wide to design, conduct, and interpret experiments that conform to the latest regulatory standards and requirements.
Regulatory Requirements
The choice of transporter experiments to be performed for a new chemical entity or new molecular entity (NCE/NME) depends on several factors, including pharmacokinetic properties, indication and patient population, and chemical structural information. However, it is by no means required to study all transporters in all cases. We work closely to avoid unnecessary and costly experiments with our clients, designing and performing transporter studies based on all available data and in light of specific compound information. While guidance documents on transporter-drug interaction studies differ in many aspects, a general guide to the required assays for EMA (Europe), FDA (United States), and PMDA (Japan) is shown in the table below.
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Inhibition studies |
Substrate studies |
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|---|---|---|---|---|---|---|
|
Transporter |
EMA |
FDA |
PMDA |
EMA* |
FDA |
PMDA |
|
yes |
yes |
yes |
consider |
yes |
yes |
|
|
yes |
yes |
yes |
consider |
yes |
yes |
|
|
prefer |
no |
no |
consider |
no |
no |
|
|
MRPs |
no |
no |
no |
consider |
no |
no |
|
yes |
yes |
yes |
consider |
≥25% of total clearance is active renal |
≥25% of total clearance is active renal |
|
|
yes |
yes |
yes |
consider |
≥25% of total clearance is active renal | ≥25% of total clearance is active renal | |
|
yes |
yes |
yes |
Yes, if hepatic clearance ≥25% total clearance |
Yes, if hepatic clearance ≥25% total clearance, or hepatic uptake is clinically important |
Yes, if hepatic clearance ≥25% total clearance, or unknown |
|
|
yes |
yes |
yes |
Yes, if hepatic clearance ≥25% total clearance | Yes, if hepatic clearance ≥25% total clearance, or hepatic uptake is clinically important | Yes, if hepatic clearance ≥25% total clearance, or unknown | |
|
consider |
no |
no |
consider |
no |
no |
|
|
yes |
yes |
yes |
consider |
Yes, if active renal clearance is ≥25% systemic clearance |
Yes, if active renal clearance is ≥25% systemic clearance |
|
|
consider |
yes |
yes |
consider |
Yes, if active renal clearance is ≥25% systemic clearance |
Yes, if active renal clearance is ≥25% systemic clearance |
|
|
consider |
yes |
yes |
consider |
Yes, if active renal clearance is ≥25% systemic clearance |
Yes, if active renal clearance is ≥25% systemic clearance |
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Sources: EMA Guideline on Investigation of Drug Interactions (2012); FDA Guidance for Industry: In Vitro Drug Interactions Studies – Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions (2020); PMDA Guideline on drug interaction for drug development and appropriate provision of information (2018).
Note: EMA guideline states that in the event that active renal, biliary or gut wall secretion is estimated to account for more than 25% of drug elimination, then attempts should be made to identify the transporter(s) involved.
Transporter Studies for Metabolites
Both FDA and EMA guidance documents state conditions in which metabolites should also be investigated for transporter-mediated drug-drug interactions. According to the EMA guideline, if active secretion is the major elimination pathway of a metabolite with significant ( ≥50% of total effect) target activity or a major contribution to off-target (adverse) effects, attempts should be made to identify the transporter(s) involved. Furthermore, if active secretion is the major elimination pathway of a metabolite with significant ( ≥50% of total effect) target activity or a major contribution to off-target (adverse) effects, attempts should be made to identify the transporter(s) involved. It is noted in the FDA guidance that some phase II metabolites can be better substrates or inhibitors of various transporters, which can lead to higher chance of drug-drug interactions than the parent drug. FDA thus recommends that the drug-drug interaction potential of a metabolite as a substrate or inhibitor of major drug transporter should be assessed on a case-by-case basis using the same principles and strategies that are applied for the parent drug.
Regulatory Guidelines
ICH draft M12 Guideline on Drug Interaction Studies, 2022
