Drug Interaction Studies
Drug interaction studies provide valuable insights into a drug’s ADME properties and potential risks, helping drug developers optimize dosing regimens and ensure patient safety. Our comprehensive portfolio of in vitro assays is designed to meet global regulatory drug-drug interaction (DDI) guidelines, and our analysis of enzyme and transporter mediated DDIs provide key data for successful planning and design of clinical DDI studies.
IND-Enabling Packages
In Vivo Studies Per Year
In Vitro Studies Per Year
DDI Testing Capabilities
WuXi AppTec is a global solution provider in DDI testing, providing both metabolism and transporter-mediated drug interaction studies. Our platform meets the requirements of different stages of drug discovery and development, including hit-to-lead finding, lead optimization, preclinical candidate identification, and preclinical research investigational new drug(IND) filing.
Metabolism-Mediated Drug Interaction Studies
Metabolism-mediated drug interactions involve identifying the primary routes of drug elimination and evaluating the role of relevant metabolic enzymes in drug disposition through enzyme metabolic reaction phenotyping experiments. Besides that, Drug interactions include examining how a drug may affect metabolic enzymes, specifically through enzyme inhibition or induction experiments. DDIs occur when one drug, referred to as the “precipitant,” affects the metabolic or pharmacokinetic behavior of a co-administered drug, known as the “object.”
- If the precipitant inhibits a cytochrome P450 (CYP) enzyme, it can reduce the metabolic clearance of the object that is primarily metabolized by that CYP.
- If the precipitant induces the CYP, it will enhance the clearance of the object that is primarily metabolized by that CYP.
- If the object is a prodrug that is converted to its active form by a CYP, the actions of inhibiting or activating precipitants will decrease or increase the serum concentrations of the active drug, respectively.
- Inhibition of CYP enzymes can lead to toxic side effects, which may be mitigated by adjusting treatment regimens.
In Vitro Models for Evaluating
Metabolism-Mediated DDI Testing
Drug interactions may lead to severe adverse effects, which lead to some drugs being terminated at an early stage of development or even withdrawn from the market. WuXi AppTec’s DDI platform provides tier-based DDI assays, which meet the requirements of different stages of drug discovery and development, including hit-to-lead, lead optimization, preclinical candidate selection, and preclinical research, supporting IND filing.
Cytochrome P450 enzyme reversible inhibition test
Assesses whether a compound temporarily inhibits CYP450 enzymes, affecting drug metabolism without permanent inactivation.
Reversible inhibition test of human uridine diphosphate glucuronosyltransferases using human liver microsomes
Evaluates whether a compound temporarily inhibits UGT enzymes, impacting drug metabolism without causing permanent enzyme inactivation.
Reversible inhibition test of human uridine diphosphate glucuronosyltransferases using recombinant enzymes
Evaluates whether a compound temporarily inhibits UGT enzymes, impacting drug metabolism without causing permanent enzyme inactivation.
Cytochrome P450 enzyme Time-dependent inhibition test
Evaluates whether a compound causes gradual, often irreversible inhibition of CYP450 enzymes over time, potentially leading to prolonged drug-drug interactions.
Cytochrome P450 Enzyme Metabolic Reaction Phenotyping Experiment
Identifies which specific CYP450 enzymes are responsible for metabolizing a particular compound.
Metabolic Reaction Phenotype of Human Uridine Diphosphate Glucuronosyltransferases
Identifies which specific UGT enzymes are responsible for the glucuronidation of a particular compound.
Cytochrome P450 Enzyme Metabolic Reaction Phenotyping Experiment
Evaluates whether a compound induce the mRNA and/ or activity of CYP450 enzymes, potentially accelerating drug metabolism.
Transporter-Mediated Drug Interaction Studies
Transporters are a group of carrier proteins that can influence a drug’s pharmacokinetics, pharmacodynamics, and toxicological properties. Transporters can affect the absorption, distribution, elimination, and other in vivo processes of drugs, affecting the efficacy and safety of drugs and playing an essential role in drug interactions (1). Usually, in vitro testing is the first step in assessing transporter-mediated DDIs, which are recommended by FDA, NMPA, EMA, and ICH et al (Table 1).
Regulatory Guidance for Transporter Investigation
ABC Transporters
ATP-binding cassette (ABC) transporters are membrane proteins that use ATP energy to transport various molecules across cellular membranes.
SLC Transporters
Solute carrier (SLC) transporters are membrane proteins that facilitate the movement of ions, nutrients, and drugs across cellular membranes via passive or secondary active transport.
Transporter Models for In Vitro DDI Studies
WuXi AppTec’s in vitro transporter platform provides various in vitro models for assessing transporter mediated DDIs. We can assess substrates or inhibitors of specific transporters using cell based and vesicles models, evaluate transport mechanisms and determine hepatocytic uptake clearance.
Cell-Based Transporter Models
Cell-based models use live cells engineered to express specific transporters, allowing for the assessment of transporter activity, drug permeability, and interactions in a more biologically relevant environment, and evaluation of drug transport mechanisms.
Non-Cell-Based Transporter Models
Non-cell based transporter models involve membrane vesicles isolated from cells that contain the transporter of interest. These models focus on direct transporter activity without the complexity of a full cellular system.
References
- Giacomini, K.M. et al. Membrane transporters in drug development. Nature reviews drug discovery 9, 215-236 (2010)
- Food and Drug Administration Center for Drug Evaluation and Research (2020). Clinical Drug Interaction Studies —Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry (FDA Maryland)
- 药物相互作用研究技术指导原则（试行）(2021, 国家药监局药审中心)
- Guideline on the Investigation of Drug Interactions (2013, EMA)
- ICH HARMONISED GUIDELINE M12 (2024, ICH)
Frequently Asked Questions
What is DDI?
A DDI occurs when one drug affects the pharmacokinetics, metabolism, or efficacy of another co-administered drug, potentially altering its efficacy or safety.
Why is DDI important for DMPK testing?
Studying DDIs is critical in DMPK to understand how drugs may interact within the body and to predict possible adverse effects.
How do DDIs affect the ADME processes of drugs?
DDIs can alter the absorption, distribution, metabolism, or excretion (ADME) of a drug, leading to changes in its concentration and action in the body. This may result in decreased therapeutic efficacy or increased toxicity.
What types of DDIs are commonly studied?
Pharmacokinetic interactions affect the drug’s concentration in the body by influencing ADME processes, while pharmacodynamic interactions alter the drug’s effects at its target site. Both types are important to study, as they can lead to significant clinical consequences.
How do DDIs impact drug absorption?
DDIs can affect drug absorption by altering gastrointestinal pH, influencing transporter proteins, or causing drug-binding interactions within the gut. These changes may decrease or increase the amount of drug reaching systemic circulation.
What role does enzyme inhibition/induction play in DDIs, particularly with cytochrome P450 (CYP) enzymes?
Enzyme inhibition can slow the metabolism of a drug, leading to increased levels and potential toxicity, while enzyme induction accelerates metabolism, possibly reducing drug efficacy. Cytochrome P450 enzymes, especially CYP3A4, are often involved in these interactions.
How do transporters (e.g., P-glycoprotein) influence DDIs?
Transporters like P-glycoprotein can limit drug absorption or promote drug excretion, and their inhibition or induction can significantly alter drug concentrations. This can lead to either enhanced drug action or increased risk of adverse effects.
What are the clinical implications of DDIs in drug safety and efficacy?
Clinically, DDIs can lead to unexpected side effects, reduced therapeutic outcomes, or even life-threatening conditions. Understanding DDIs helps optimize drug dosing regimens and avoid harmful combinations.
What in vitro and in vivo models are used to study DDIs?
In vitro models often include liver microsomes or recombinant enzymes to assess enzyme-mediated interactions and cell lines or vesicles expressing transporters to assess transporter‑mediated interactions, while in vivo models in animals or human trials evaluate the overall pharmacokinetic effects. Both approaches provide critical insights into DDI potential during drug development.
What regulatory guidelines exist for DDI studies?
Regulatory agencies, such as the FDA and EMA, provide specific guidelines for evaluating DDIs during drug development. These guidelines include testing for enzyme-mediated interactions, transporter effects, and clinical trial design for DDI assessment.
How do DDI studies inform dosage adjustments or drug labeling?
DDI studies provide data that can lead to dosage modifications or warnings in drug labeling to ensure safe and effective use. These adjustments are crucial for minimizing the risk of adverse interactions in patients taking multiple medications.
What are the challenges in predicting DDIs during early drug development?
Predicting DDIs early is challenging due to limited in vivo data and the complexity of drug metabolism pathways. In vitro studies can suggest potential interactions, but real-world effects may vary based on individual patient factors.