WHITE PAPER

Assessing Transporter-based
Drug-Drug Interactions
By Jingjing Yu and Isabelle Ragueneau-Majlessi
Assessing drug-drug interactions (DDIs) is critical to drug development. This assessment helps ensure
that patients can safely take new medications with their existing treatments.
Modulation of cytochrome P450 (CYP) enzymes or drug transporters causes most DDIs. These
interactions can significantly impact the pharmacokinetics and pharmacodynamics of drugs, leading to
variations in therapeutic efficacy and potential adverse effects. Thus, it is recommended to evaluate DDIs
early in drug development to identify and mitigate any risks associated with concurrent medication use.

THE CHALLENGES OF ASSESSING with multiple transporters and/or enzymes, complicating

TRANSPORTER-MEDIATED DDIs extrapolating results to other drugs.

Evaluating transporter-mediated DDIs can be more complex For a new molecular entity (NME), interpreting
than assessing CYP-mediated DDIs. This is primarily due “precipitant” DDI study results with a transporter substrate
to insufficient current transporter-specific marker substrates requires understanding the NME’s transporter inhibition
and/or inhibitors. A panel of drugs has been recommended properties and its effect on metabolizing enzymes.
as clinical substrates or inhibitors of various drug Conversely, “object” DDI studies involving a transporter
transporters. Unfortunately, these drugs frequently interact inhibitor should consider its effects on the NME’s transport
and metabolism/elimination.

Figure 1. Clinically important uptake and efflux transporters in plasma. Galetin et al (2024).Membrane transporters in drug development and as
determinants of precision medicine | Nature reviews drug discovery

certara.com 2
HOW CAN I STREAMLINE DRUG-DRUG revealed that your NME inhibited BCRP with an IC50 value of
INTERACTION RISK ASSESSMENT? 10 µM in transfected cells. Inhibiting BCRP may increase the
systemic exposure of BCRP substrate drugs. This increased
The Certara Drug Interaction Database (DIDB) offers a drug exposure could cause adverse drug reactions. Thus,
unique and comprehensive collection of in vitro and clinical assessing the clinical relevance of such in vitro findings is
drug metabolism and transporter data from the biomedical critical.
literature and drug approval packages. The DIDB platform
features a DDI Calculator developed based on the basic and As an initial step, use the DIDB DDI Calculator to evaluate
mechanistic static prediction models. Leveraging the DIDB the drug’s in vivo inhibition potential of BCRP. It can be used
can provide valuable insights into transporter-based drug for multiple CYP enzymes and transporters and includes
interactions. the calculation modules and various thresholds proposed
in the ICH M12 DDI final guideline (2024)1. At present, FDA,
This case study highlights the value of the DIDB in assessing EMA, PMDA, and NMPA DDI guidances are also included for
an NME’s inhibitory potential on the transporter BCRP in reference.2,3,4,5
vivo (i.e., as precipitant). In this use case, in vitro studies

Transporter inhibition

Figure 2. The DDI Calculator

shows that an investigational
drug inhibits the BCRP
transporter to the extent that
regulators will require it to be
addressed.

In this case study, the basic model suggests that your NME target patient population’s likely concomitant medications.
might inhibit BCRP in the gut when orally administered at This step will help determine the need for a clinical trial.
a clinical dose. So, should you design a clinical trial with Here are the steps you can take using DIDB:
a BCRP substrate to evaluate the clinical significance?
First, identify known clinical BCRP substrates. Use the
Alternatively, is there a method to further assess the
DIDB platform to perform a thorough literature search
situation before conducting a clinical study? Or can you
and analysis. The DDI Marker Studies Knowledgebase, DDI
avoid the trial altogether?
summaries, and pharmacogenetic data can help you quickly
Let’s assess the potential DDI risk for your NME with the identify known clinical BCRP substrates.

DDI Marker Studies Knowledgebase

Figure 3. Partial view of BCRP substrates in the DDI Marker Studies Knowledgebase, accessible at DIDB / Resources after logging into DIDB.

certara.com 3
DDI summaries including drug class, DDI risk level, and elimination routes

Figure 4. Partial view of BCRP

substrates in DDI summaries, accessible
at DIDB / Monographs / DDI Summaries
after logging into DIDB

Pharmacogenetic data with literature citations:

Figure 5. Partial views of BCRP substrates pharmacogenetic query results, accessible at DIDB / Queries / Pharmacogenetic Queries after logging into DIDB

Usually, this step is enough to obtain a list of the drugs you BCRP inhibitor. If you need a comprehensive list, search for
need to consider. However, some substrates might not be all in vitro BCRP substrates.
listed as they may lack clinical evidence for a known clinical

certara.com 4
In Vitro

Figure 6. DIDB’s search function allows users to identify all known drugs with in vitro evidence for interacting with various transporters.

Next, you can select likely concomitant medications. Select concomitant medications relevant to your patient population
from the list of BCRP substrates identified above for further review.

Figure 7. Excerpt from ICH M12 DDI guideline.1

Then perform a comprehensive data review. Utilize For example, let’s consider the kinase inhibitor sunitinib
the DIDB’s in vitro and clinical datasets to review each as a possible concomitant medication of your NME in
concomitant medication. Examine all relevant in vitro and the indicated patient population. Some in vitro evidence
in vivo DDI data, pharmacogenetic data, and product labels. suggests that sunitinib is a BCRP substrate (efflux ratios of
Are there specific recommendations for concomitant use 2.3-12 in transfected cells. The presence of a BCRP inhibitor
with BCRP inhibitors or for different BCRP subpopulations? significantly reduced the efflux ratios.)6,7,8,9
Additionally, gather information on any metabolizing Sunitinib is also a substrate of P-gp (similar efflux ratios as
enzymes and other transporters involved in the disposition BCRP), MRP4, and OATP1B1 in vitro. No DDI studies with
of the concomitant medications of interest. known BCRP clinical inhibitors are available. However,
pharmacogenetic analyses show that sunitinib AUC was
Finally, draw conclusions on risk and clinical significance.
2.30- to 3.21-fold higher in subjects with BCRP poor
Based on the evidence available, assess the clinical significance
function compared to normal function, and 1.26- to 1.79-
of potential drug interactions of your NME with these
fold higher in those with decreased function after multiple
concomitant medications and the role of BCRP inhibition.
dosing.10,11

certara.com 5
This data suggests that sunitinib is a clinical substrate of For instance, the DIDB Pharmacokinetic profiles below
BCRP with approximately 2-fold increases in exposure show that sunitinib is metabolized by CYP3A, with an
expected in case of significant inhibition. Additionally, if estimated contribution to CL/F of 34% based on the DDI
your NME also inhibits or induces CYP enzymes, you can study with ketoconazole. If your NME also affects CYP3A
review the metabolism data for sunitinib. activity, the impact of CYP3A and BCRP inhibition would
further increase the DDI effect of the NME.

Pharmacokinetic profile

Figure 8. The DIDB provides pharmacokinetic profiles for drugs that include important information on PK parameters (clearance, half-life, Tmax,
etc.) as well as physiochemical properties.

certara.com 6
The DIDB provides pharmacokinetic profiles for drugs that Because of its breadth of content (in vitro, in vivo,
include important information on parameters (clearance, pharmacogenetics), the DIDB platform is invaluable for
half-life, Tmax, etc.) as well as physiochemical properties. assessing the clinical risk of transporter-mediated DDIs.
This tool can also help drug developers determine whether
Evaluate other drugs that are likely to be co-administered
a clinical trial is necessary.
with your NME. If you find that the impact of BCRP-mediated
DDI is high in your expected patient population, then you Certara also offers a range of simulation software and
probably need to perform a dedicated clinical DDI study with consulting services to support drug development programs.
a recommended BCRP substrate. This study will allow you to Its new, interdisciplinary Center of Excellence in Drug
quantify the clinical risk and propose recommendations for Interaction Science paves the way for experts to collaborate
concomitant use of common BCRP substrates. to solve even the most complex DDI situations from early
development to regulatory approval.

Request a free trial or book a demo now to see DIDB in action.

Visit: certara.com/drug-interaction-database-didb/demo/
Or email: [email protected].

References
1. ICH Harmonized Guideline Drug Interaction Studies M12 (final version, adopted 21 8. S Tang, J Lagas, N Lankheet, B Poller, M Hillebrand, H Rosing, J Beijnen, A Schinkel.
May 2024) Brain accumulation of sunitinib is restricted by P-glycoprotein (ABCB1) and breast
cancer resistance protein (ABCG2) and can be enhanced by oral elacridar and sunitinib
2. FDA In Vitro Drug Interaction Studies – Cytochrome P450 Enzyme- and Transporter- coadministration. Int J Cancer. 2012 Jan 01, 130 (1) 223-33. (PMID 21351087)
Mediated Drug Interactions Guidance for Industry (January 2020)
9. H Liu, L Huang, Y Li, T Fu, X Sun, Y Zhang, R Gao, Q Chen, W Zhang, J Sahi, S
3. EMA Guideline on the Investigation of Drug Interactions (final, 21 June 2012) Summerfield, K Dong. Correlation between Membrane Protein Expression Levels and
Transcellular Transport Activity for Breast Cancer Resistance Protein. Drug Metab
4. PMDA Guideline on Drug Interaction for Drug Development and Appropriate Dispos. 2017 May, 45 (5) 449-456. (PMID 28209803)
Provision of Information (February 2019)
10. T Mizuno, M Fukudo, T Terada, T Kamba, E Nakamura, O Ogawa, K Inui, T Katsura.
5. NMPA Guidance on Drug Interaction Studies (draft, September 2020) Impact of genetic variation in breast cancer resistance protein (BCRP/ABCG2) on
sunitinib pharmacokinetics. Drug Metab Pharmacokinet. 2012, 27 (6) 631-9. (PMID
6. T Mizuno, T Terada, T Kamba, M Fukudo, T Katsura, E Nakamura, O Ogawa, K Inui. 22673043)
ABCG2 421C>A polymorphism and high exposure of sunitinib in a patient with renal cell
carcinoma. Ann Oncol. 2010 Jun, 21 (6) 1382-1383. (PMID 20348146) 11. C Narjoz, A Cessot, A Thomas-Schoemann, J L Golmard, O Huillard, P Boudou-
Rouquette, A Behouche, F Taieb, J P Durand, A Dauphin, R Coriat, M Vidal, M Tod, J
7. B Poller, E Wagenaar, S Tang, A Schinkel. Double-transduced MDCKII cells to study Alexandre, M A Loriot, F Goldwasser, B Blanchet. Role of the lean body mass and of
human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) interplay pharmacogenetic variants on the pharmacokinetics and pharmacodynamics of sunitinib
in drug transport across the blood-brain barrier. Mol Pharm. 2011 Apr 04, 8 (2) 571-82. in cancer patients. Invest New Drugs. 2015 Feb, 33 (1) 257-68. (PMID 25344452)
(PMID 21309545)

About Certara
Certara accelerates medicines using biosimulation software, technology, and services to transform traditional
drug discovery and development. Its clients include more than 2,400 biopharmaceutical companies, academic
institutions, and regulatory agencies across 66 countries. Learn more at certara.com.