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Drug-Drug Interaction (DDI) Studies

What is a Drug Interaction?

The rise of polypharmacy has led to an increasing number of patients taking an increasing number of medications. This creates problems when the drugs affect one another’s exposure. In some cases, this can lead to toxic side effects or a lack of clinical efficacy. Commonly referred to as drug-drug interactions, this phenomenon usually occurs when a drug affects the expression or function of a metabolic enzyme or transporter. Since metabolism is the primary mechanism for elimination of most drugs, changes in the enzymes responsible for drug metabolism can lead to undesirable increases (or decreases) in the plasma concentration of drugs.

Drug-Drug Interaction Classification

Drugs are colloquially classified as either victims or perpetrators of drug-drug interactions. As their names imply, victims are drugs directly affected by DDIs, while perpetrators are drugs that cause DDIs. Perpetrators can be further classified as either inducers or inhibitors. Inducers increase the expression and/or function of metabolic enzymes primarily through the activation of receptors involved in the regulation of gene transcription. Inhibitors decrease the expression and/or function of metabolic enzymes primarily through substrate competition.

Types of DDI Studies

There are many considerations that go into which nonclinical and clinical drug interaction studies should be performed. Protocol development depends on several factors including (but not limited to) dosing regimen, exposure-related safety concerns, and the mechanism of the DDI. The FDA has issued several guidance documents related to the conduct of DDI studies. Listed below are some of the most common types of DDI studies.


Evaluating Metabolism-Based Drug Interactions: Various test systems can be used, including recombinant CYP enzymes, subcellular liver microsomes, and human liver tissue. They can help identify the enzymes that metabolize an investigational drug and determine if the drug is an enzyme inhibitor or inducer. Each system has advantages and disadvantages, so the choice must be tailored for the specific drug and application.

Evaluating Transporter-Mediated Drug Interactions: Test systems include membrane vesicles and cell-based systems. These studies can be used to determine if an investigational drug is a substrate or an inhibitor of various transporters. Regardless of the system, transport assays require consistent validation and the inclusion of positive and negative controls.


Index Perpetrators and Index Substrates: Prospective studies specifically designed to detect DDIs are the most likely to inform regulatory decision-making regarding a new drug. In this type of study, known enzymatic inhibitors or substrates are co-administered with the investigational drug to simulate worst-case scenarios. Most of the time, these index compounds are not therapeutically relevant, but the results can be used to extrapolate the findings to clinically relevant medications.

Expected Concomitant Use Drugs: Studies using drugs that treat the same condition for which the investigational drug is being studied or that treat common comorbidities associated with the condition are directly relevant to the clinical utility of the investigational drug. This type of study is often used to investigate transporter-mediated DDIs, as only a few substrates or perpetrators of transporters fulfill the criteria of an index drug.

When to Execute DDI Studies in Development Programs

Drug-drug interaction studies can be performed in all phases of drug development, although the earlier typically the better. The results of preclinical DDI studies combined with clinical PK data can often be used to simulate clinical DDI studies, saving time and money.

Dynamic mechanistic models, including PBPK models, can support decisions on when and how to conduct a clinical DDI study. These models can also predict the magnitude of DDI in special patient populations that would otherwise be difficult to recruit into a study.

Patients frequently use more than one medication at a time, thus investigating drug-drug interactions is essential to drug development. Nuventra has experience designing and analyzing DDI studies at all phases of development. We work closely with our clients to find the best strategies for their program.

Contact one of our senior consultants today for tailored advice on your DDI study or learn how to potentially avoid a DDI study with the use of modeling and simulation. Learn more by reading our case study titled, “Avoiding a DDI Study in Pediatric Populations.”

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