Therapeutic Protein Drug Interactions: A White Paper From the International Consortium for Innovation and Quality in Pharmaceutical Development

Abstract

Typically, therapeutic proteins (TPs) have a low risk for eliciting meaningful drug interactions (DIs). However, there are select instances where TP drug interactions (TP‐DIs) of clinical concern can occur. This white paper discusses the various types of TP‐DIs involving mechanisms such as changes in disease state, target‐mediated drug disposition, neonatal Fc receptor (FcRn), or antidrug antibodies formation. The nature of TP drug interaction being investigated should determine whether the examination is conducted as a standalone TP–DI study in healthy participants, in patients, or assessed via population pharmacokinetic analysis. DIs involving antibody–drug conjugates are discussed briefly, but the primary focus here will be DIs involving cytokine modulation. Cytokine modulation can occur directly by certain TPs, or indirectly due to moderate to severe inflammation, infection, or injury. Disease states that have been shown to result in indirect disease–DIs that are clinically meaningful have been listed (i.e., typically a twofold change in the systemic exposure of a coadministered sensitive cytochrome P450 substrate drug). Type of disease and severity of inflammation should be the primary drivers for risk assessment for disease–DIs. While more clinical inflammatory marker data needs to be collected, the use of two or more clinical inflammatory markers (such as C‐reactive protein, albumin, or interleukin 6) may help broadly categorize whether the predicted magnitude of inflammatory disease–DI risk is negligible, weak, or moderate to strong. Based on current knowledge, clinical DI studies are not necessary for all TPs, and should no longer be conducted in certain disease patient populations such as psoriasis, which do not have sufficient systemic inflammation to cause a meaningful indirect disease–DI.

Clinical Significance of Therapeutic Peptide and Protein Drug Interactions: A Call to Action

“…As a rule of thumb, the smaller the peptide the more potential DDIs can be expected to mimic conventional small molecules, whereas DDIs for large proteins will typically be determined by different, complex biological mechanisms, such as cytokine modulation and disease state 1 . Coutant and colleagues from the IQ consortium postulate that for therapeutic proteins that modulate cytokine release and action, disease state and severity are the primary determinants DDIs 2 . On the basis of this, they recommend, for example, that clinical DDI studies for therapeutic proteins are not necessary in diseases like psoriasis 2 …”

“…Coutant and colleagues from the IQ consortium postulate that for therapeutic proteins that modulate cytokine release and action, disease state and severity are the primary determinants DDIs 2 . On the basis of this, they recommend, for example, that clinical DDI studies for therapeutic proteins are not necessary in diseases like psoriasis 2 …”

“…This working group surveyed 10 pharma companies involved in the development of peptide drugs to better understand the type and timing of DDI studies commonly undertaken for such therapeutics, and compiled a database containing in vitro and clinical DDI data from submission packages for peptide drugs approved between January 2008 and August 2021 1 . In parallel, Coutant et al 2 . compiled a position paper on therapeutic proteins’ DDIs on behalf of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ; http://www.iqconsortium.org), which originated as a response to the 2020 US Food and Drug Administration (FDA) draft guidance 3 …”

“…Both White Papers are a call to action to develop a better understanding of the scientific basis and clinical significance of DDIs for therapeutic peptides and proteins. Currently, there is a lack of a consistent approach in drug development, limited understanding of the unique mechanisms underlying therapeutic peptide and protein DDIs, and a one‐size‐fits‐all regulatory framework which does not consider the actual clinical significance of potential DDIs on a case‐by‐case basis 1,2 . Specific next steps proposed by the authors are: Gather more information about indirect disease—DDIs, including their effects and which disease states are of clinical concern; Consider collecting inflammatory biomarker data in phase II or phase III clinical trials of therapeutic peptides and proteins that treat inflammatory disease; Investigate and develop new physiologically‐based pharmacokinetic tools to aid in understanding the time course and mechanisms of certain types of DDIs 3 ; Publishing positive and negative results from peptide/protein DDI studies; Application of complex in vitro organ‐on‐a‐chip systems; Analyzing the physicochemical properties for a large set of diverse compounds in correlation with in vitro DDI parameters related to CYPs and transporters to determine the relevance of different in vitro DDI studies. …”

Assessment of the drug–drug interaction potential for therapeutic proteins with pro‐inflammatory activities

“…Therapeutic proteins (TPs) with pro‐inflammatory activities are a class of TPs with the properties either as pro‐inflammatory cytokines, such as peginterferon, or as pro‐inflammatory cytokine modulators, such as blinatumomab. By definition, TPs with pro‐inflammatory activities could result in persistent or transient elevation of cytokine levels in the body, therefore, administration of TPs with pro‐inflammatory activities could lead to DDIs with co‐administered drugs owing to the cytokine‐drug interaction 6,7 . Recent US Food and Drug Administration (FDA) draft guidance on “Drug‐drug interaction assessment for therapeutic proteins” laid out recommendations regarding assessing DDI risks for TPs 8 .…”