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.