PBPK modelling to predict drug-biologic interactions with cytokine modulators: Are these relevant and is IL-6 enough?

Abstract

Drugs that modulate cytokine levels are often used for the treatment of cancer as well as inflammatory or immunological disorders. Pharmacokinetic drug-biologic interactions (DBI) may arise from suppression or elevation of cytochrome P450 (CYP) enzymes caused by the increase or decrease in cytokine levels following administration of these therapies. There is in vitro and in vivo evidence that demonstrates a clear link between raised interleukin (IL)-6 levels and CYP suppression, in particular CYP3A4. However despite this, the changes in IL-6 levels in vivo rarely lead to significant drug interactions (AUC and Cmax ratios < 2-fold). The clinical significance of such interactions therefore remains questionable and is dependent on the therapeutic index of the small molecule therapy. Physiologically-based pharmacokinetic (PBPK) modelling has been used successfully to predict the impact of raised IL-6 on CYP activities. Beyond IL-6, published data show little evidence that IL-8, IL-10, and IL-17 suppress CYP enzymes. I n vitro data suggest that IL-1β, IL-2, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ can cause suppression of CYP enzymes. Despite in vivo there being a link between IL-6 levels and CYP suppression, the evidence to support a direct effect of IL-2, IL-8, IL-10, IL-17, IFN-γ, TNF-α or vascular endothelial growth factor (VEGF) on CYP activity is inconclusive. This commentary will discuss the relevance of such drug-biologic interactions and whether current PBPK models considering only IL-6 are sufficient. Significance Statement This commentary summarizes the current in vitro and in vivo literature regarding cytokine-mediated CYP suppression and compares the relative suppressive potential of different cytokines in reference to IL-6. It also discusses the relevance of drug-biologic interactions to therapeutic use of small molecule drugs and whether current PBPK models considering only IL-6 are sufficient to predict the extent of drug-biologic interactions.