Current status of prediction of IL-6 mediated cytochrome P450 activity modulation using in vitro data and PBPK...

This review focuses on use of in vitro data and physiologically based pharmacokinetic (PBPK) modeling to predict disease-drug and therapeutic-protein-drug interactions for Cytochrome P450 CYP substrates mediated by interleukin-6 (IL-6). We review current understanding of the mechanisms of inflammatory IL-6 release (both with and without drug treatment), and provide an overview of the in vitro models for assessing CYP suppression by IL-6. Furthermore, past applications and current status of PBPK modeling in this context were comprehensively reviewed. We then highlight a recently published, more mechanistic PBPK model that treats IL-6 as a therapeutic protein and links CYP suppression to the IL-6-receptor complex concentration in the liver and gut interstitial spaces. This new model demonstrates good predictive performance across various patient populations and is able to simulate clinical outcomes based on a mechanistic pharmacokinetic model integrating known IL-6 receptor biology. Therefore we anticipate increased impact on regulatory decisions. However, gaps remain in understanding IL-6 kinetics and the translation of in vitro data to in vivo predictions and we suggest that further progress will be made by applying mechanistic modeling to guide future experimental work and generate a better understanding of IL-6's influence on co-administered small molecule drugs.