Utilization of physiologically‐based pharmacokinetic model to assess disease‐mediated therapeutic protein‐disease‐drug interaction in immune‐mediated inflammatory diseases

It is known that interleukin‐6 (IL‐6) can significantly modulate some key drug‐metabolizing enzymes, such as phase I cytochrome P450s (CYPs). In this study, a physiologically‐based pharmacokinetic (PBPK) model was developed to assess CYPs mediated therapeutic protein drug interactions (TP‐DIs) in patients with immune‐mediated inflammatory diseases (IMIDs) with elevated systemic IL‐6 levels when treated by anti‐IL‐6 therapies. Literature data of IL‐6 levels in various diseases were incorporated in SimCYP to construct respective virtual patient populations. The modulation effects of systemic IL‐6 level and local IL‐6 level in the gastrointestinal tract (GI) on CYPs activities were assessed. Upon blockade of the IL‐6 signaling pathway by an anti‐IL‐6 treatment, the area under plasma concentration versus time curves (AUCs) of S‐warfarin, omeprazole, and midazolam were predicted to decrease by up to 40%, 42%, and 46%, respectively. In patients with Crohn’s disease and ulcerative colitis treated with an anti‐IL‐6 therapy, the lowering of the elevated IL‐6 levels in the local GI tissue were predicted to result in further decreases in AUCs of those CYP substrates. The propensity of TP‐DIs under comorbidity conditions, such as in patients with cancer with IMID, were also explored. With further validation with relevant clinical data, this PBPK model may provide an in silico way to quantify the magnitude of potential TP‐DI in patients with elevated IL‐6 levels when an anti‐IL‐6 therapeutic is used with concomitant small‐molecule drugs. This model may be further adapted to evaluate the CYP modulation effect by other therapeutic modalities, which would significantly alter levels of proinflammatory cytokines during the treatment period.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Interleukin‐6 (IL‐6) may significantly modulate some key drug‐metabolizing enzymes, including phase I cytochrome P450s (CYPs). A physiologically‐based pharmacokinetic (PBPK) model was developed to predict the impact of elevated IL‐6 level and anti‐IL‐6 mAb treatment on multiple CYP enzymes in patients with rheumatoid arthritis.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The aforementioned PBPK model was expanded to assess potential therapeutic protein drug interactions (TP‐DIs) between anti‐IL‐6 treatment and CYP substrate drugs in different immune‐mediated inflammatory disease (IMID) populations with elevated IL‐6 levels. For the inflammatory bowel disease (IBD) populations, modulation effects from elevated IL‐6 levels in the local gastrointestinal tract were taken into consideration. The potential additive modulation effect on CYPs from concomitant cancer‐IMID situation was also assessed. Furthermore, simulations at different hypothetical IL‐6 levels were performed to identify the IL‐6 levels, which would result in weak, moderate, and strong CYP modulation effects based on the definitions in the US Food and Drug Administration (FDA) drug‐drug interaction guidance.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The PBPK platform model was expanded to assess the potential TP‐DIs during anti‐IL‐6 treatment in several IMIDs including systemic lupus erythematosus, ulcerative colitis, Crohn’s disease, type 1 diabetes, and cancer‐IMID comorbidity. The high local IL‐6 levels in patients with IBD were predicted to result in extra inhibition effect on the abundances of intestinal CYPs. Patients with cancer‐IMID manifested further decrease in systemic exposures of CYP substrate drugs compared with patients with IMID only. Cutoff values of IL‐6 level which would result in different levels of CYP modulation effect were identified.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This PBPK model approach may serve as conceptual framework and workflow process to evaluate the modulation effect on CYPs in patients by therapeutic modalities which can significantly result in altered levels of proinflammatory cytokines during the treatment period.