Drug-drug interactions may occur when a patient is taking multiple medications simultaneously for one or more conditions. When taken at the same time, some drugs can affect other drugs’ exposures leading to unintended reactions, toxic side effects, or in some cases, a lack of clinical efficacy. These unintended reactions are known as drug-drug interactions (DDIs). As the global phenomenon of polypharmacy (e.g., patients taking multiple medications simultaneously) continues to rise, it is important for drug developers to understand how drugs interact with one another. There are different types of clinical and nonclinical studies that drug developers use to test whether a DDI may occur and whether it may be significant enough to warrant a dosage adjustment, precaution, or contraindication. A familiarity with the different ways that DDIs can impact patient safety and drug efficacy is essential for creating a drug development plan that optimizes the chance of optimal safety and efficacy for an investigational drug.
What is a Drug Interaction?
A “drug interaction” can be an interaction with another drug (drug-drug interaction), an interaction with a disease (drug-disease interaction), or an interaction with food or alcohol. Extrinsic factors (drug, food, or alcohol) or intrinsic factors (disease) can both have an effect on a drug’s pharmacokinetics (PK) or pharmacodynamic (PD) properties which can then cause a drug interaction. Most investigational drugs have a “therapeutic window” or a target range of exposure. When the drug concentration goes below the therapeutic window, efficacy wanes and when drug concentration goes above the therapeutic window, adverse events become more likely. Drug interactions of any type have the potential to push a drug’s exposure either above or below the therapeutic window, which can lead to undesired consequences to the patient.
Types of Drug Interactions
Any factor that influences a drug’s PK or PD can cause a drug interaction. Most often, drug interactions refer to the effect of intrinsic or extrinsic factors on PK. However, in some cases there are factors that impact a drug’s PD as well. Below are some common drug interactions:
- Drug-over the counter: similar to a DDI, over the counter medications may influence a drug’s PK or PD
- Drug-food: the presence of food at the site of absorption in the gastrointestinal tract may accelerate or impede the absorption process, resulting in increased, decreased, or delayed concentration levels
- Drug-alcohol: alcohol can interact with many drugs that work in the central nervous system, most commonly exacerbating side effects of CNS-depression
- Drug-disease: disease states can cause profound physiological changes that can alter a drug’s PK or PD
- Drug-laboratory: drugs can interfere with lab tests by causing false positives or false negatives to occur
Drug-Drug Interactions
DDIs usually occur when a drug affects the expression or function of a metabolic enzyme or transporter. Since metabolism is the primary mechanism of elimination for most drugs, changes in the enzymes responsible for drug metabolism can lead to undesirable increases (or decreases) in the plasma concentration of drugs.
Classifying Drug-Drug Interactions
Classifying DDIs provides important insights into how to predict, detect, and avoid adverse interactions. Drugs are informally classified as either victims or perpetrators of DDIs. 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 of metabolic enzymes or transporters, leading to reduced concentrations of the victim drug. Inhibitors decrease the function of metabolic enzymes or transporters, leading to increased concentrations of the victim drug.
Types of Drug-Drug Interaction Studies
There are different types of DDI studies that should be conducted depending on what phase of development you are in. Some DDI studies will be conducted during the nonclinical phase and others during the clinical phase. 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 guidance documents related to conducting DDI studies.
Nonclinical: Evaluating Metabolism-Based Drug Interactions
Test systems can be used to evaluate metabolism-based drug interactions, including recombinant CYP enzymes, subcellular liver microsomes, and human liver tissue. They can help identify the metabolites and metabolizing enzymes of an investigational drug. The data from these studies can be used in turn to determine the potential that the investigational drug may be the victim of a DDI in the clinic. In vitro studies can also determine if a drug is an enzyme inhibitor or inducer (and, therefore, a possible perpetrator of a DDI). Each system has advantages and disadvantages, so the choice must be tailored for the specific drug and application.
Nonclinical: Evaluating Transporter-Mediated Drug Interactions
These studies can be used to determine if an investigational drug is a substrate and therefore a potential victim, or an inhibitor, and therefore a likely perpetrator, of various transporters. Test systems include membrane vesicles and cell-based systems. Regardless of the system, transport assays require consistent validation and the inclusion of positive and negative controls.
Clinical: 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. If the PK of an investigational drug is not altered when administered concomitantly with an index inhibitor or substrate, then the investigational drug would not be expected to be involved in these types of DDIs.
Clinical: Expected Concomitant Use Drugs
Often, investigational drugs are intended to be added to an existing therapeutic regimen including other mediations for a given condition. These other medications can be studied in healthy volunteers who are simultaneously administered the investigational drug to directly assess the presence of a DDI.
In-Silico Modeling
DDIs can also be predicted using in-silico modeling techniques. Physiologically-based pharmacokinetic (PBPK) models are a common modeling approach used to investigate potential DDIs. This type of model is used to understand the impact of concomitant dosing of drugs and incorporates detailed data of human physiology, enzyme, and transporter abundance in each tissue. Modeling tools, such as PK-Sim (a commercially available, open-source software) often contain PBPK data from commonly-used DDI perpetrators and victims that allow models to be constructed without collecting separate DDI data. The benefit of an in-silico modeling approach is that the possibility for DDIs can be evaluated before going into clinical studies and evaluated in difficult to study patient populations such as pediatric or pregnant populations. The information gained from DDI simulations can help guide the direction of clinical DDI studies.
When to Execute Drug-Drug Interaction Studies
DDI studies can be performed in all phases of drug development, although typically, the earlier you can conduct DDI studies in your program, the better. The results of nonclinical DDI studies combined with clinical PK data can often be used to simulate some clinical DDI studies through modeling. In-silico modeling can be performed at almost any stage of drug development but will typically yield the most useful results once nonclinical studies have been conducted. If the data is available, clinical DDI studies can be used to validate the DDI model. Other useful data sources include in-vitro or in-vivo data to parameterize the magnitude of the interaction between the drug and the relevant enzymes or transporters. If the investigational drug is to be administered in parallel with other medications that are suspected to cause a DDI, the DDI should be characterized before carrying out late-phase studies, otherwise, potential perpetrators as well as victim drugs may be prohibited in the study population.
Allucent’s Drug-Drug Interaction Study Services
Investigating drug-drug interactions is essential to drug development because patients frequently use more than one medication at a time. Allucent has experience designing and analyzing DDI studies at all phases of drug development. We work closely with our clients to find the best strategies for each program. In some cases, it is possible to avoid a DDI study altogether with modeling and simulation techniques such as PBPK modeling. Contact one of our senior experts for tailored advice on your DDI study or to learn how to potentially avoid a DDI study with the use of modeling and simulation.
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