Advancements in in vitro technologies and analytical instrumentation over the past decade allows scientists to apply a variety of in vitro based assays designed to rapidly assess risk-liability, such as drug-drug interactions (DDI), one of the factors contributing to both current high attrition rates and delays in development.
In vitro assays are ideal in early phase development as they typically can be conducted quickly and involve low compound usage – requiring just milligrams of material. This makes in vitro assays ideal for early discovery programs, where typically, only small amounts of compound are available. These specific in vitro assays can be efficiently combined into a “risk assessment package” which can be employed early in drug development as a de-risking paradigm to aid informed decision-making prior to major investment decisions on new drug candidates.
Examining drug-drug interaction (DDI)
A drug-drug interaction occurs when the pharmacokinetics (concentration of drug in the blood) of one drug (the victim) is changed by another drug (the perpetrator). Many patients are taking more than one medication at any one time and this is when DDI can occur which can affect efficacy and can sometimes cause fatal toxicity. If a drug is considered too high a risk to the victim or perpetrator, even with benefits of the drug for patients, it still has a risk of not being approved by the regulatory authorities due to potential DDIs in humans.
How important is DDI assessment?
The assessment of pharmacokinetic-based DDIs is a major element of early de-risking drug development. Drugs with a high DDI potential (particularly as a victim drug) may be at risk of non-approval, excessive labeling or post-market withdrawal. Following the publication of the FDA regulatory guidance changes in 2012, DDI is quickly becoming a scientific discipline in its own right, sitting alongside other traditional areas in the Pharma industry such as toxicology and DMPK.
Find out more information about EMA guidelines on the in the investigation of drug interactions.
It is critical that the contributing factors in the increased importance of DDI assessment are taken into consideration. One of the major influences is an aging population. As individuals live longer, the occurrence of patients being prescribed multiple concurrent medications (polypharmacy) is increasing. Consequently, the risk of adverse drug reactions due to DDIs is also growing.
It is also necessary to obtain certain kinds of DDI information in order to run other studies, clinical studies included. For example, with a human AME study, it is essential to have phenotyping data present to be able to identify which enzymes are involved in the metabolism of a specific drug. Securing this information will help drug developers to understand the potential risks and hurdles earlier in the development stage.
If a compound is effectively de-risked from having a high DDI potential, having gone through a series of in vitro testing which results in a lower negative, provides drug developers with the highest confidence to invest in a molecule.
De-risking also assists in the entire processing of in/out licensing which becomes much more straight forward with regards to making informed decisions around the compound, once it has undergone full DDI assessment.
Essentially, DDI assessment will help define the risks to a product in terms of recognizing whether the indication can stand the risk. For example, is the drug first in class and does it meet an unmet need?
To explore DDI assessment in more detail, read our white on de-risking drug development.
What are some of the regulatory recommendations?
To test a new drug for DDI potential, regulatory authorities recommend the initial use of a range of in vitro studies (basic models) designed to assess interactions of new drugs as both a victim and perpetrator of DDIs:
- Perpetrator drug studies - to assess how the test drug will affect other medications - these studies assess the potential inhibition and induction of important drug metabolizing enzymes such as CYP and UGT and transporter proteins by the test drug
- Victim drug studies - to assess how the test drug will be affected by other medications - these studies determine which enzymes and transporter proteins are involved in the clearance of the test drug (substrate phenotyping interactions).
To highlight the importance of DDI assessment in one instance, key findings from the preclinical and clinical drug interaction studies presented in new drug and biological license applications approved by the FDA express that new drugs approved in 2014 were extensively evaluated for metabolism and transport-based DDIs and clinically significant DDIs were observed for almost half of the new drug molecules. This stresses just how vital the assessment of DDIs is to getting new drugs approved by the FDA.
To discover the regulatory recommendations to assess interactions of new drugs in more detail and understand why drugs have drug-drug interactions, listen to the webinar ‘Drug-drug interactions’ by guy Webber.
About the author
Guy Webber, Scientific Manager, In vitro and drug-drug interaction sciences at Envigo, has 25 years’ experience in Pharma and Contract Research, working on hundreds of drug molecules for many different clients.