Clinical and in-vitro studies for potential drug-drug interactions

The US Food and Drug Administration (FDA) have finalised two guidances which provide recommendations to drug developers on how to evaluate drug-drug interactions (DDI) for investigational new drugs (IND), through in-vitro and clinical studies.

Both guidances focus on drug interactions associated with the cytochrome P450 enzyme and associate transported substrates. Together, they describe a “systematic risk-based approach to evaluation and communication of DDIs”.

In-vitro Drug Interaction Studies

The first guidance discusses approaches to be used to evaluate the DDI potential of IND and how they can inform future clinical studies. If the results of in-vitro assessment and pharmacokinetic data of a DDI suggest that a clinical study is required, the sponsor should then refer to the clinical guidance below.

“Evaluating the DDI potential of an investigational new drug involves identifying the principal routes of the drug’s elimination; estimating the contribution of enzymes and transporters to the drug’s disposition; and characterising the effect of the drug on enzymes and transporters.”

The guidance then further discusses approaches for the evaluation of metabolism-mediated and transporter-mediated drug interactions, and the DDI potential of associated metabolites.

Clinical Drug Interaction Studies

The second guidance discusses various DDI study designs and considerations for CYP-mediated interactions and transported-mediated reactions identified at the in-vitro stage. It helps sponsors of INDs to determine the essential DDI information to communicate in labelling of the final product. Other factors which could impact drug interactions include patient genetics, smoking and alcohol.

DDIs are a critical factor in a drug’s overall benefit-risk profile. Clinically relevant DDIs should be identified during drug development, known at the time of approval, included in labelling and monitored persistently.