Physiologically Based Pharmacokinetic Modeling To Predict Drug-Biologic Interactions with Cytokine Modulators: Are These Relevant and Is Interleukin-6 Enough?

Drugs that modulate cytokine levels are often used for the treatment of cancer as well as inflammatory or immunologic disorders. Pharmacokinetic drug-biologic interactions (DBIs) may arise from suppression or elevation of cytochrome P450 (P450) enzymes caused by the increase or decrease in cytokine levels after administration of these therapies. There is in vitro and in vivo evidence that demonstrates a clear link between raised interleukin (IL)-6 levels and P450 suppression, in particular CYP3A4. However, despite this, the changes in IL-6 levels in vivo rarely lead to significant drug interactions (area under the curve and C-max 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) modeling has been used successfully to predict the impact of raised IL-6 on P450 activities. Beyond IL-6, published data show little evidence that IL-8, IL-10, and IL-17 suppress P450 enzymes. In vitro data suggest that IL-1 beta, IL-2, tumor necrosis factor ( TNF)-alpha, and interferon (IFN)-gamma can cause suppression of P450 enzymes. Despite in vivo there being a link between IL-6 levels and P450 suppression, the evidence to support a direct effect of IL-2, IL-8, IL- 10, IL-17, IFN-gamma, TNF-alpha, or vascular endothelial growth factor on P450 activity is inconclusive. This commentary will discuss the relevance of such drug-biologic interactions and whether current PBPKmodels considering only IL-6 are sufficient. SIGNIFICANCE STATEMENT This commentary summarizes the current in vitro and in vivo literature regarding cytokine-mediated cytochrome P450 suppression and compares the relative suppressive potential of different cytokines in reference to interleukin ( IL)- 6. It also discusses the relevance of drug-biologic interactions to therapeutic use of small molecule drugs and whether current physiologically based pharmacokinetic models considering only IL- 6 are sufficient to predict the extent of drug- biologic interactions.

Automated summary

Drugs that modulate cytokine levels are commonly used for cancer treatment and inflammatory or immunologic disorders. There is clear evidence linking elevated IL-6 levels to P450 suppression, although the clinical significance of these interactions remains uncertain. PBPK modeling has been successful in predicting the impact of raised IL-6 on P450 activities. However, evidence regarding the direct effect of other cytokines on P450 activity is inconclusive.