Regulatory Guidance for Drug Interaction Studies

SOLVO Transporter Studies for Regulatory Submission

New regulatory guidelines for the investigation of drug interactions were released in 2017: The US Food and Drug Administration (FDA) published the draft guidance for comment in October, 2017. The final version of the European Medicines Agency (EMA) Guidelines on the Investigation of Drug Interactions came into effect on the 1st of January, 2013. The Japanese Ministry of Health, Labour, and Welfare (MHLW) published the tentative guidance in January, 2014. The European Medicines Agency (EMA), the US Food and Drug Administration (FDA) and The Japanese Ministry of Health, Labour, and Welfare (MHLW) require a variety of Drug Transporter studies be performed for any New Chemical/Molecular Entity (NCE/NME). SOLVO assists companies world-wide with performing these studies, interpreting the regulatory requirements, study design, and reporting. SOLVO offers the broadest array of transporter assays commercially available to assist customers with meeting regulatory requirements.

Regulatory Requirements

The choice of transporter experiments to be performed for an NCE/NME largely depends on its pharmacokinetic properties. It is by no means required to study all transporters in all cases. To prevent generation of unnecessary data and expense, SOLVO works closely with its clients to design and perform transporter studies based on available data and their specific compound information.

 

Inhibition studies

Substrate studies

Transporter

EMA

FDA

Japan

EMA*

FDA

Japan

P-gp (MDR1)

yes

yes

yes

consider

yes

yes

BCRP

yes

yes

yes

consider

yes

yes

BSEP

prefer

consider

no

consider

consider

no

MRPs

no

consider

no

consider

consider

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

OATP1B1

yes

yes

yes

≥25% of elimination  hepatic

≥25% of total clearance is hepatic or biliary

≥25% of total clearance is hepatic or biliary

OATP1B3

yes

yes

yes

OCT1

consider

no

no

consider

no

no

OCT2

yes

yes

yes

consider

≥25% of total clearance is active renal

≥25% of total clearance is active renal

MATE1

consider

yes

yes

consider

≥25% of total clearance is active renal

consider

MATE2

consider

yes

yes

consider

≥25% of total clearance is active renal

consider

Sources: EMA Guideline on Investigation of Drug Interactions, July 2012, FDA Draft Guidance on Drug Interaction Studies, February 2012, The Ministry of Health, Labour, and Welfare (MHLW), Japan, 2014
*EMA Guideline states if renal or biliary/gut wall secretion separately account for more than ≥25% of drug elimination, attempts should be made to identify the transporter(s) involved in active secretion

Important note: The EMA requirement to identify transporters responsible for major renal and biliary/gut wall secretion may result in the need for drug developers consider transporters beyond those listed in the table above. To assist customers in cases where transporter responsible for observed pharmacokinetics is not easily identified, SOLVO provides the broadest portfolio of commercial transporter assays available. Transporters such as PEPTs, OCTNs, and additional OATPs are currently offered and we are continually adding new transporter assays to our portfolio. Visit our website regularly for in depth information on all the transporter services and products offered.

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SOLVO solutions and capabilities

Efflux transporters

Studying interactions with efflux transporters is complicated due to intracellular binding sites. The ability of compounds to reach the binding site always has to be kept in mind when designing efflux transporter studies. Considering the passive permeability of a compound and the purpose of the assay, a suitable assay system should be carefully chosen. SOLVO provides a variety of efflux transporter assays suitable for evaluating transporter interactions of compounds with differing permeability characteristics:

Type of study

Inhibition

Substrate

Permeability of TA

Low

High

Low

Moderate

High

P-gp (MDR1)

VT

VT, MDCKII-MDR1

VT

MDCKII-MDR1

ATPase*

BCRP

VT

VT, MDCKII-BCRP

VT

MDCKII-BCRP

ATPase

BSEP

VT

VT

VT

VT#

-

MRPs

VT

VT

VT

VT#

ATPase

Abbreviations: VT – Vesicular Transport, TA - Test Article
*Note that the ATPase assay is an indirect assay and therefore not considered definitive. Still there are numerous examples of high permeability substrates that are only identified as substrates in the ATPase assay (e.g. Verapamil-MDR1; Reference: Von Richter et al; Naunyn-Schmiedeberg’s Arch Pharmacol (2009) 379:11-26).
#Cellular assays may be preferable for these compounds but are currently not available. Uptake transporters
Solvo offers a wide-range uptake transporter models. Leveraging our extensive characterization and validation procedures, Solvo provides our clients with class-leading inhibition and substrate assay services. As IC50s can depend on the substrate used, SOLVO aims to provide a choice of probe substrates for each uptake transporter inhibition assay. Check our website or our SOLVO Uptake Transporter Services flyer for more information. Please find below the relevant regulatory documents related to drug transporter studies released up to present:

Regulatory Guidelines

In Vitro Metabolism- and Transporter Mediated Drug- Drug Interaction Studies Guidance for Industry, 2017 FDA DDI Draft Guidance

FDA Guidance for Industry Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing and Labeling, 2006

EMA Guideline on the Investigation of Drug Interactions, 2010 EMA Draft Guideline 2010

FDA Guidance for Industry Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations, 2012

EMA Guideline on the Investigation of Drug Interactions, 2012 (effective from the 1st of January, 2013)

Japanese Guideline on the Investigation of Drug Interactions, 2014

Transporter Decision Trees

FDA Transporter Decision Tree

EMA Transporter Decision Trees

Japanese Transporter Decision Trees

Related Recommendations

Recommendations by pharma, academic and regulatory experts (International Transporter Consortium, ITC) are introduced in Nature Reviews Drug Discovery (2010) Volume 9 /March: 215:236

FDA Advisory Committee Approved Recommendation for Routine Transporter DDI Assessment for New Drugs - FDA’s Advisory Committee for Pharmaceutical Science and Clinical Pharmacology voted to recommend NCE’s to be assessed for transporter mediated drug-interactions for the seven clinically relevant transporters in the ITC Transporter White Paper. Transcript from the FDA Advisory Committee for Pharmaceutical Science and Clinical Pharmacology Meeting

Recommendations by the 2nd International Transporter Consortium (ITC) Workshop are introduced in Clin. Pharmaco. Ther. 2012 Nov;92(5):553-6

The ITCW2 proposed expansion of transporters for evaluation during drug development. "Besides the original seven transport proteins recommended in the 2012 FDA Draft Drug Interaction Guidance, MATEs (MATE1, MATE2) were proposed for prospective investigation in drug development. In addition, MRP2 and BSEP inhibition were recommended for retrospective studies based on preclinical and clinical observations.”

Benefits of working with Solvo

  1. Facilities to work with radiolabeled compounds (High throughput)
  2. Bioanalytical method development and validation
  3. Validation data, upon request
  4. Multiple probe substrates per transporter (Number of substrates varies per transporter)
  5. Multiple reference inhibitors per transporter (Clinically relevant where available)
  6. Full study reports (Company specific templates can be used)
  7. Quality Assurance
    1.  ISO 9001
    2. GLP study services available in the US through XenoBiotic Laboratories, Inc.
  8. Possibility for QA audit