Clinical Drug Interaction Studies: compare drug substrate (victim) concentrations in the absence 

and presence of a potential perpetrator drug in vivo.

Parent Drug Substrate Concentration Results Identifi ed DDI

Drug A alone 

 (in absence of Drug B)

Interaction Due to Induction:

• Drug A is the victim1

 drug

• Drug B is the perpetrator2

 drug.

Drug B causes a decrease in Drug A

concentrations and, therefore, is an

inducer.

1 The term victim refers to the drug

 whose exposure may or may not 

 be changed by a perpetrator drug.

2 The term perpetrator refers to the 

 drug that causes an eff ect on the

 victim (substrate) drug by inhibiting

 or inducing enzymes or transporters.

Parent Substrate Concentration

Time

Drug A + Drug B

!

What is recommended in this guidance?

The final guidance Clinical Drug Interaction Studies —Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions provides considerations for evaluating pharmacokinetic (PK) 

interactions mediated by cytochrome P450 (CYP) enzymes or transporters. The goals of studies 

that investigate CYP enzyme- and transporter-mediated drug interactions include the following:

• Determine whether the investigational drug alters the PK of other drugs

• Determine whether other drugs alter the PK of the investigational drug

• Determine the magnitude of changes in PK parameters

• Determine the clinical significance of the observed or expected drug-drug interactions (DDIs)

• Inform the appropriate management and prevention strategies for clinically significant DDIs

Clinical Drug Interaction Studies — 

Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions

Final Guidance for Industry

To learn more about clinical drug interaction studies, read the guidance: 

https://www.fda.gov/media/134581/download

www.fda.gov
To learn more about clinical drug interaction studies, read the guidance: https://www.fda.gov/media/134581/download

www.fda.gov

Why is This Guidance Important?

Patients frequently use more than one medication at a time. Unanticipated, unrecognized, or 

mismanaged DDIs are an important cause of morbidity and mortality associated with prescription 

drug use and have occasionally caused the withdrawal of approved drugs from the market. This ?

guidance provides recommendations for evaluating DDIs during drug development and 

determining essential information to communicate in labeling. 

How Should Drug-Drug Interactions Be Presented in the Labeling?

The Prescribing Information should include a summary of essential DDI information, and the DRUG 

INTERACTIONS and CLINICAL PHARMACOLOGY sections of drug labeling should include the majority of the 

information is often included in varying levels of detail in other sections of the labeling (e.g., BOXED 

WARNING, DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and/or WARNINGS AND PRECAUTIONS 

sections), and must be discussed in more detail in the DRUG INTERACTIONS section (§ 201.57(c)(8)(i)).

Drug-Drug Interaction Studies: Prospective Studies vs. Retrospective Evaluations

Types of

DDI Studies

Index Studies

To test whether an investigational drug is a 

victim of DDIs, sponsors should use index

perpetrators. To test whether the 

investigational drug is a perpetrator,

sponsors should use index substrates, which

when administered with a strong inhibitor for 

currently recommended index drugs for 

inhibitors, or inducers) is maintained on the

FDA’s Web site for Drug Development and

Drug Interactions.

In Silico Studies

Physiologically based PK (PBPK) models can 

be used in lieu of some prospective DDI 

studies. Before using a PBPK modeling

or weak perpetrator drugs on the exposure of 

an investigational drug, sponsors should 

verify the models using human PK data and 

information from DDI studies that used 

strong index perpetrators.

Concomitant-Use Studies

Sponsors should evaluate concomitant 

medications that are likely to interact with the 

investigational drug in the clinical practice

setting (e.g., add-on drug therapies or 

treatments for common co-morbidities) using 

a risk-based approach that considers the drug 

interaction mechanisms and the clinical

exposure. The relevant concomitant 

medications for study include those used to 

treat the same condition for which the

investigational drug is being studied or those 

used to treat common co-morbidities in the 

patient population.

3 FDA’s Website on Drug Development and Drug

Interactions can be found at 

https://www.fda.gov/drugs/drug-interactions-labeling/

drug-development-and-drug-interactions.

Drug-Drug Interaction Studies: Prospective Studies vs. Retrospective Evaluations

Regulatory decision-making generally requires prospective studies specifically designed to detect DDIs as 

a major objective. Retrospective evaluation of drug concentrations from studies not designed to evaluate 

DDIs rarely includes sufficient precision to provide an adequate assessment.

www.fda.gov

3

 FDA’s Website on Drug Development and Drug Interactions 

can be found at

 https://www.fda.gov/drugs/drug-interactions-labeling/

 drug-development-and-drug-interactions.

To learn more about clinical drug interaction studies, read the guidance:

https://www.fda.gov/media/134581/download

Types of

DDI Studies
Guidance Snapshots are a communication tool and are not a substitute for the guidance document. To learn 

more about clinical drug interaction studies, read the guidance: 

https://www.fda.gov/media/134581/download

Background About the Guidance

DDIs are a significant but avoidable cause of morbidity and mortality 

associated with prescription drugs. The rate of adverse drug reactions 

increases significantly for patients who take four or more medications. 

Currently, close to 40 percent of the U.S. population receive 

prescriptions for four or more medications. FDA issued this guidance 

to provide best practices for clinical studies evaluating DDIs and 

recommendations for determining essential information to 

communicate in labeling to health care providers. 

Guidance Recap Podcast – Hear Highlights 

Straight From FDA Staff

Speaker:

Dr. Kellie Reynolds, Director of the Division of Infectious Disease Pharmacology 

in the Office of Clinical Pharmacology

During Clinical Development: After conducting in vitro drug metabolism and drug transporter studies, sponsors should determine the need for and timing of clinical DDI studies with respect to 

other studies in their clinical development program. Sponsors should assess the DDI potential before 

the product is administered to patients who are likely to take concomitant medications that could 

interact with the investigational drug. Furthermore, sponsors should collect enough DDI information 

to prevent patients from being unnecessarily excluded from any clinical study because of 

their concomitant medication use. 

Drug Development Timeline – When to Apply 

the Guidance Recommendations?

CLICK HERE TO LISTEN

CLICK HERE TO READ TRANSCRIPT

Basic

Research

Prototype

Design or

Discovery

Preclinical

Development

Clinical Development

Phase I Phase 2 Phase 3

FDA Filing/

Approval

Post-Market/

Post-Approval 

}

Studies