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FDA guides drug-drug interaction studies for therapeutic proteins

Posted 10 August 2020 | By Kari Oakes 

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A new draft guidance from the US Food and Drug Administration (FDA) gives industry direction in how to assess drug-drug interactions for therapeutic proteins.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In particular, TPs that themselves are inflammatory cytokines – the draft guidance gives peginterferon as an example – can cause downregulation of cytochrome P450 (CYP) enzymes.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.
In the case of proinflammatory cytokines, “the sponsor should determine the time course and extent of this increase in cytokine levels to help determine the need for a DDI study, the design of a study, and an appropriate mitigation strategy, if necessary,” says the guidance.
If the sponsor believes there is low potential for clinically significant DDI for a TP that modulates proinflammatory cytokines, they may provide a justification for not providing corresponding labeling language. The justification, says FDA, should include the magnitude of drug effect by the TP, how exposure levels of CYP substrates can vary across the indicated population, and what effects are seen in other agents, or in the same agent in other disease states that have at least as great an inflammatory burden as the sought indication.
DDI evaluation for mechanisms unrelated to proinflammatory cytokines should be considered in several situations, says the draft guidance. These include scenarios where a TP’s effect on physiology can alter a co-administered medication’s pharmacokinetics, or when a co-administered medication would impact the TP target. DDI evaluation should also be considered when the function of neonatal Fc (FcRn) is affected by co-administered medications.

Another circumstance in which DDI should be considered is when the TP is co-administered with immunosuppressing drugs such as methotrexate, if the TP’s pharmacokinetics are affected by immunogenicity. In all these instances, the document provides guidance on when the TP should be evaluated as a “perpetrator” or a “victim” in the DDI.
The guidance also reviews considerations for antibody-drug conjugates (ADCs), with instructions for how to evaluate the small molecule drug component of the conjugate with regard to systemic exposure. “In many cases, the systemic concentration might be too low to act as a perpetrator. It might be necessary to evaluate the small molecule component (administered as an ADC) as a victim drug,” says the agency.
The draft guidance advises early consultation with FDA to refine whether studies will be conducted, and when in vitro or animal studies might supplement – but not likely supplant – clinical studies: “Sponsors should consider the DDI risk of their product early in development and summarize their DDI program at milestone meetings with the FDA. Potential discussion topics at these meetings include the need for and planning, timing, and study design of DDI evaluations for the investigational drug,” according to the draft guidance.
A decision tree supplementing the guidance gives an overview of under which circumstances sponsors should consider DDI studies.
The guidance is intended to supplement two other final guidances regarding in vitro and clinical drug interaction studies for cytochrome P450-mediated drug interactions.


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