Regulatory Guidance for Drug Interaction Studies

SOLVO Transporter Studies for Regulatory Submission

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.

 

Inhibition studies

Substrate studies

Transporter

EMA

FDA

PMDA

EMA*

FDA

PMDA

P-gp (MDR1)

yes

yes

yes

consider

yes

yes

BCRP

yes

yes

yes

consider

yes

yes

BSEP

prefer

no

no

consider

no

no

MRPs

no

no

no

consider

no

no

OAT1

yes

yes

yes

consider

≥25% of total clearance is active renal

≥25% of total clearance is active renal

OAT3

yes

yes

yes

consider

≥25% of total clearance is active renal ≥25% of total clearance is active renal

OATP1B1

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

OATP1B3

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

OCT1

consider

no

no

consider

no

no

OCT2

yes

yes

yes

consider

Yes, if active renal clearance is ≥25% systemic clearance

Yes, if active renal clearance is ≥25% systemic clearance

MATE1

consider

yes

yes

consider

Yes, if active renal clearance is ≥25% systemic clearance

Yes, if active renal clearance is ≥25% systemic clearance

MATE2

consider

yes

yes

consider

Yes, if active renal clearance is ≥25% systemic clearance

Yes, if active renal clearance is ≥25% systemic clearance

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.

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Regulatory Guidelines

FDA Guidance for Industry: In Vitro Drug Interactions Studies – Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions, 2020

EMA Guideline on Investigation of Drug Interactions, 2012

PMDA Guideline on drug interaction for drug development and appropriate provision of information, 2018