USA – FDA guides drug-drug interaction studies for therapeutic proteins

A new draft guidance from the US Food and Drug Administration (FDA) gives industry direction in how to assess drug-drug interactions for therapeutic proteins.

The guidance, issued jointly by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) recommends that sponsors use a “systematic, risk-based” approach to determine whether their therapeutic protein candidates for investigational new drug applications (INDs) and biologic license applications (BLAs) require drug-drug- interaction studies.

The draft document covers therapeutic proteins (TPs) licensed as therapeutic biological products, but FDA notes that the general concepts could be applicable to other biological products, including biological products regulated by CBER such as cellular and gene therapies.

In considering the potential for drug-drug interactions (DDIs), sponsors should consider the potential mechanisms for DDIs between therapeutic proteins (TPs) or between TPs and small molecules.

In particular, TPs that themselves are inflammatory cytokines – the draft guidance gives peginterferon as an example – can cause downregulation of cytochrome P450 (CYP) enzymes. This has the effect of increasing exposure levels to drugs that pass through this metabolic pathway, since their CYP metabolism is decreased. Conversely, cytokine inhibitors can boost CYP expression and reduce exposure for drugs that are CYP substrates…