When a patient is taking multiple medications concurrently for one or more conditions, drug-drug interactions (DDIs) may occur. As the global phenomenon of polypharmacy (i.e., patients taking multiple medications simultaneously) continues to rise, it is important for drug developers to understand how drugs interact with one another. There are various types of clinical and nonclinical studies that drug developers use to investigate if a DDI may occur clinically and whether it may be significant enough to warrant a dosage adjustment, precaution, or contraindication in the prescribing information. Familiarity with the an investigational drug’s DDI profile is essential for creating a drug development plan and dose rationale that optimizes clinical safety and efficacy.
What is a Drug Interaction?
DDIs occur when the effects of one drug are altered by the presence of another drug. This interaction can change the way one or both drugs work – either affecting their clinical efficacy or increasing the risk of side effects. DDIs often occur when a drug affects the function of a metabolic enzyme or transporter. Changes in the enzymes or transporters involved in drug metabolism and disposition can lead to undesirable increases or decreases in the systemic concentrations of drugs. Most investigational drugs have a “therapeutic window” or a target range of exposure. When the drug concentration falls below the therapeutic window, efficacy wanes and when the concentration exceeds the therapeutic window, adverse events become more likely. Therefore, when the plasma concentration of a drug is pushed either above or below its therapeutic window, undesired consequences to the patient can occur.
Some DDIs occur due to pharmacokinetic (PK) interactions, and some occur due to pharmacodynamic (PD) interactions. PK DDIs are the focus of this article.
- Pharmacokinetic interaction – when a drug affects the absorption, distribution, metabolism, or excretion of another drug (e.g., interaction results in increased or decreased drug concentrations potentially leading to toxicity or lack of efficacy). Examples:
- Compound A inhibits an enzyme that metabolizes Compound B. Compound B systemic concentrations rise above the therapeutic window, leading to toxicity.
- Compound C raises the gastric pH. Compound D requires an acidic environment to be properly absorbed, therefore Drug D concentrations do not reach efficacious levels.
- Pharmacodynamic interactions – occur when the pharmacological effect of one drugs is affected by another drug; often described as when two drugs have additive, synergistic, or antagonistic effects at the same or related target sites (e.g., interaction results in increased or decreased therapeutic or adverse effects of the drug).Examples
- Compound E and Compound F individually can cause an increase in the risk of bleeding. When used together, the risk of bleeding is further increased.
- Compound G counteracts the effect of Compound H, leading to a reduction in overall efficacy of Compound H.
Classifying Drug-Drug Interactionson.
The classification of DDIs allows for important insights into how to predict, detect, and avoid adverse interactions. Drugs are classified as either objects or precipitants of DDIs, which have been historically referred to as victims or perpetrators, respectively. As their names imply, objects (often referred to as ‘substrates’) are affected by other drugs, while precipitants have an effect on other drugs. . Substrates can be further classified as moderate sensitive and sensitive, and precipitants can be further classified as either inducers or inhibitors. Inducers increase the expression of metabolic enzymes or transporters, leading to reduced concentrations of the object drug. Inhibitors decrease the function of metabolic enzymes or transporters, leading to increased concentrations of the object drug. If a drug is identified as an inhibitor or inducer, it can be further classified as a strong, moderate, or weak inhibitor or inducer based on its effect on a sensitive substrate. A drug can be both a precipitant and a substrate for various enzymes and transporters. For example, a drug can be an inhibitor of a certain enzyme while also being an object of various enzyme or transporter interactions.
Types of Drug-Drug Interaction Studies
There are different types of Drug-Drug Interaction Studies that may be conducted depending on the phase of drug development. Some DDI studies are conducted during the nonclinical phase and others during the clinical phase. Nonclinical studies can help identify the risk of a drug acting as either an object or a precipitant of clinical DDIs. There are many considerations that go into which nonclinical and clinical drug interaction studies should be performed and when – such as the need to prohibit concomitant use of precipitants in clinical studies. The FDA issued a guidance document related to conducting DDI studies with useful information pertaining to PK DDIs of small molecules.
Nonclinical: Evaluating Metabolism-Based Drug Interactions
Test systems can be used in in vitro studies to evaluate metabolism-based drug interactions, including recombinant cytochrome P450 (CYP) enzymes, subcellular liver microsomes, and human liver tissue. These test systems can help identify the metabolites and metabolizing enzymes of an investigational drug. Each system has advantages and disadvantages, so the choice must be tailored for the specific drug and application. Data from these drug-drug interaction studies can be used to determine whether the investigational drug may be the object of a DDI in the clinic.These studies can also determine if a drug is an inhibitor or inducer of CYP enzymes or UDP-glucuronosyltransferases (UGTs)and, therefore, a possible precipitant of a DDI.
Nonclinical: Evaluating Transporter-Mediated Drug Interactions
In vitro studies can also be used to determine whether an investigational drug is a substrate (make it a potential object) or an inhibitor or an inducer(make it a likely precipitant) of various transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Test systems include membrane vesicles and cell-based systems. After assessing transporter mediated DDIs in nonclinical studies, clinical studies may be considered if an investigated drug is considered as a potentially clinically relevant substrate, inhibitor, or inducer of a transporter.
Nonclinical: DDI Potential of Metabolites
Metabolites may also cause DDIs that impact drug safety and efficacy. Nonclinical studies may be used to determine if a drug’s metabolites are objects, inhibitors or inducers.
Clinical: Design Options
Prospective studies specifically designed to detect DDIs are the most likely to inform regulatory decision-making regarding a new drug. Prospective clinical DDIstudies can be performed with the assessment of DDIs as the primary objective, typically in healthy participants (standalone studies), or as part of larger clinical studies in patients (nested studies). DDI data collected as part of a nested study is typically evaluated using population PK. Study design decisions and protocol development depend on several factors including (but not limited to) dosing regimen, exposure-related safety concerns, and the mechanism of the DDI.
Clinical: Index Precipitants and Index Substrates
Depending on what is known about an investigational drug and likelihood for potential clinical DDIs, DDI studies may include assessments of the investigational drug’s effect on other drugs (investigational drug as the precipitant), or the effect of other drugs on the investigational drug (investigational drug as the object/substrate). Index precipitants or substrates (drugs which are known to be precipitants or substrates of certain enzymes or transporters) may be used in DDI studies to assess interactions with the investigational drug. 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.
In DDI studies designed to assess whether the investigational drug is a precipitant of a certain interaction, a known (index) substrate that interacts with CYP enzymes or transporter systems are co-administered with the investigational drug to determine if the investigational drug is a precipitant (inhibitor or inducer). If the PK of the index substrate is not altered when administered concomitantly with the investigational drug, then the investigational drug would not be expected to be involved in these types of DDIs.
In Drug-Drug Interaction Studies designed to assess whether the investigational drug is an object of a certain interaction, known (index) precipitants that interact with CYP enzymes or transporter systems are co-administered with the investigational drug, often to simulate worst-case scenarios of a DDI (i.e., with a known strong inhibitor or inducer). If the PK of an investigational drug is not altered when administered concomitantly with an index inhibitor or inducer, then the investigational drug would not be expected to be involved in the type of DDI tested.
Clinical: Expected Concomitant Use Drugs
Often, investigational drugs are intended to be added to an existing therapeutic regimen including other medications for a given condition. These other medications can be prioritized to be studied in healthy participants who are simultaneously administered the investigational drug to directly assess the presence of a DDI.
Gastric pH-Dependent Drug Interactions
Some acid-reducing agents (ARAs) can elevate the gastric pH, which may affect the bioavailability of oral drugs. Therefore, risk assessment for pH dependent DDIs should be considered in early development. If pH-dependent DDI potential is identified, a clinical study to characterize the effect of ARAs on investigational drug PK should be conducted. If a clinical study is not done, rationale is needed for why concomitant administration with ARAs that increase gastric pH is not expected to impact exposures of the investigational drug.
Drug-Drug Interactions for Therapeutic Proteins
The use of therapeutic proteins is on the rise, and these types of drugs are often used in combination with other medications. When assessing DDIs between therapeutic proteins and small molecules or between therapeutic proteins, various factors should be considered, including the potential mechanism for the interaction, disease type and severity, biological product type, clearance pathways of the therapeutic protein, and commonly co-administered drugs in the proposed patient population(s).
In-Silico Modeling
The results of nonclinical Drug-Drug Interaction Studies combined with clinical PK data can often be used to simulate clinical DDI studies through in-silico modeling. 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 as well as 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 precipitants and objects that allow models to be constructed without collecting separate DDI data. A benefit of an in-silico modeling approach is that DDI potential can be assessed before initiating clinical studies (i.e., PBPK modeling can determine if there is expected to be a clinically significant interaction with dose or administration routes specified in the model) and in some cases, can be used to avoid clinical DDI studies altogether. Additionally, DDIs can be 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 in these populations.
When to Perform Clinical Drug-Drug Interaction Studies
DDI studies can be performed in all phases of drug development, although typically, it is beneficial to conduct DDI studies earlier in development to support appropriate use of concomitant medications in later studies. . In-silico modeling can also 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 precipitants as well as object drugs may be prohibited in the study population and may influence the label with respect to use of concomitant medications.
Allucent’s DDI Studies in Drug Development
Investigating DDIs in nonclinical and clinical studies is essential to drug development, as patients in the real world 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.
About the Authors
Rachel Rozakis, PharmD, Senior Clinical Pharmacologist at Allucent has extensive experience in clinical pharmacology and scientific communications. She brings a strong track record of cross-functional contributions across therapeutic areas including neurology, cardiology, dermatology, and oncology. Rachel has played a key role in authoring and contributing to a wide range of regulatory and clinical documents, such as Investigational New Drug (IND) applications, New Drug Application (NDA) submissions, clinical study reports (CSRs), study protocols, and QT summary reports. Her scientific writing expertise supports regulatory strategy and drives the development of high-quality documentation essential for drug development and approval.
Allie Story, Clinical Pharmacology, Modeling and Simulation Intern at Allucent is a PharmD candidate at the University of North Carolina Eshelman School of Pharmacy. She brings over four years of experience in pharmaceutical manufacturing and research and development, with a focus on oncology and cell and gene therapy. At Allucent, Allie contributes to clinical pharmacology consulting projects through technical writing and scientific support, applying her background in drug development to help advance innovative therapies.
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