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.
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), 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) or reduced transporter efflux or uptake leading to changes in plasma or tissue concentrations of the parent drug or its main metabolites (e.g., in the case of transporter inhibition). 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 interactions with other therapies as well as determining if genetic polymorphisms in specific enzymes or transporters could lead to variable plasma levels within the patient population.
Regulatory DDI Studies to Support IND and NDA Submission
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 characterised in vitro test systems and accompanying well validated and positively controlled protocols to ensure the data produced are reliable and high quality.
Cyprotex is able to fully support in vitro DDI packages for submission to the FDA and EMA regulatory authorities under the following guidance documents:
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
DDI Package Services
Cyprotex have the full panel of in vitro DDI services including:
Cyprotex offer 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. 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.
Figure 1: Example of Worksheet used to Assess Possible DDI Risk using in vitro CYP Inhibition Data
Figure 2: Example of Worksheet used to Assess Possible DDI Risk using in vitro Transporter Inhibition Data
Figure 3: Example of Worksheet used to Quantitatively Predict Possible DDI Risk with the Statins as Co-Medication