Drug-Drug Interactions

Cyprotex is a specialist provider of ADME and PK services and provide a range of in vitro drug-drug interaction assays. Our expert consultants can assist you with study design, implementation and data interpretation according to the regulatory guidance including the ICH M12 guideline adopted in May 2024.

Drug-drug interactions (DDI) are a common cause of adverse reactions which can occasionally lead to serious or even fatal consequences. The incidence of DDIs is expected to escalate due to an increasing elderly population where polypharmacy is becoming more widespread.

Metabolizing enzyme-mediated drug-drug interactions can lead to either a decrease in the metabolism of the parent drug leading to elevated plasma levels (e.g. in the case of enzyme inhibition) or increased metabolism of the parent drug leading to a potential reduction in efficacy or an increased formation of a toxic metabolite (e.g. in the case of enzyme induction).

Transporter-mediated drug-drug interactions through inhibition of transporters can lead to a decrease in the efflux or uptake of the parent drug and its main metabolites leading to changes in their plasma or tissue concentrations, depending upon transporter location. For example, inhibition of efflux or uptake in the intestine will result in increased absorption and therefore exposure, or decreased absorption and therefore reduced efficacy, respectively. In contrast, inhibition of efflux or uptake in the liver or kidney will result in decreased clearance, and increased intracellular tissue concentrations, or elevated plasma concentrations, of parent drug and metabolites, respectively.

Understanding which enzymes are involved in drug metabolism (reaction phenotyping) or which transporters are responsible for the uptake or efflux of the parent drug or its main metabolites (transporter substrate identification) can be important to identify potential “victim/object” interactions with other “perpetrator/precipitant” therapies as well as determining if genetic polymorphisms in specific enzymes or transporters could lead to variable plasma levels within the patient population.

The most common types of metabolic drug-drug interactions are the inhibition and induction of the drug metabolizing enzymes. These interactions can cause increased or decreased drug exposures when two or more drugs are co-administered. For example, cytochrome P450 inhibition (CYP450) may increase the plasma levels of co-administered drugs leading to toxicity. Conversely, if a CYP450 enzyme is induced it may increase the metabolism of the co-administered compound; this can reduce plasma levels resulting in decreased efficacy or an increased formation of a toxic metabolite.

Cyprotex provides a range of services to investigate drug-drug interactions including cytochrome P450 inhibition, cytochrome P450 time dependent inhibition, cytochrome P450 induction (catalytic activity and/or mRNA assessment, plus RIS assessment), nuclear receptor activation and UGT inhibition as well as a range of other non-CYP mediated metabolism assays. Cyprotex also offer more detailed K_i service in order to determine the inhibitor affinity to the enzyme and indicate the type of inhibition observed. We can also offer a k_inact/K_I service to further characterize time dependent inhibition.

Investigating if any of the main CYP isoforms are involved in the in vitro metabolism of a drug is also important in determining if drug interactions may occur. Cyprotex provides a cytochrome P450 and UGT reaction phenotyping service as well as a non-CYP mediated reaction phenotyping service.

Understanding potential DDI before the investigational new drug reaches clinical trials in patients (e.g. Phase I in oncology, Phases II and III for other disease indications) is important for guiding the design of clinical DDI studies and for identifying possible safety issues. In vitro methods are available for this purpose and regulatory guidelines have been published which assist in the design of these in vitro studies and how the data can be used to identify DDI potential.

The data generated from in vitro DDI studies can be used to support both IND (Investigational New Drug) and NDA (New Drug Application) submissions. Although the regulatory authorities do not require these in vitro DDI studies to be performed to GLP (Good Laboratory Practice), it is important to have established well characterized in vitro test systems and accompanying well validated and positively controlled protocols to ensure the data produced are reliable and high quality.

Cyprotex and parent company Evotec are able to fully support in vitro DDI packages for submission to the regulatory authorities under the new ICH M12 guidance: 

• ICH Harmonised Guideline: Drug Interaction Studies M12

We can also comply with the following US (FDA) guidance and European (EMA) and Japanese (PMDA) guidelines:

• US FDA Guidance for Industry – Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations
• European Medicines Agency (EMA) Guideline on the Investigation of Drug Interactions
• Japanese Ministry of Health, Labour and Welfare Guideline on Drug-Drug Interactions

We have the full panel of in vitro DDI services including:

• Transporter Inhibition (Efflux and Uptake) – IC₅₀ (equivalent to K_i)
• Reversible Cytochrome P450 (CYP) Inhibition – IC₅₀ and K_i
• Time Dependent Inhibition (TDI) CYP Inhibition –  IC₅₀ shift , k_inact/K_I
• Cytochrome P450 Induction and RIS analysis
• UGT Inhibition – IC₅₀ and K_i

• Transporter Substrate Identification (Efflux and Uptake)
• Reaction Phenotyping (both CYP and non-CYP)

• Solubility
• Plasma Protein Binding
• Microsomal Binding
• Caco-2 Permeability
• Cytotoxicity
• Metabolite Profiling
• Bioanalytical Development and Feasibility
• Nuclear Receptor Activation
• HepaRG Induction

Cyprotex offers consultancy on regulatory DDI studies helping you to design the initial in vitro DDI studies as well as interpreting the in vitro data and understanding how it can be used to guide clinical DDI studies.

We have designed worksheets which can be used to assess possible qualitative DDI risk based on the regulatory recommendations and which can be formally reported as a written document.

Furthermore, we have designed worksheets for quantitative DDI risk with common co-medications such as the statins through prediction of maximum theoretical fold increases in statin AUC using both drug metabolism and transporter inhibition data. These predictions can be formally reported as a written document.