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

Abstract

Introduction: 447Discussion: 4982 Running Title: Cytokine modulated drug interactions Abbreviations: cytochrome P450 (CYP); drug-biologic interactions (DBIs); the U.S. Food and Drug Administration (FDA); drug-drug interactions (DDIs); interleukin (IL); Physiologicallybased pharmacokinetic (PBPK); rheumatoid arthritis (RA); maximum fold suppression (E min ); concentration that supports half-maximal suppression (EC 50 ); interferon (IFN); ethoxyresorufin-O-deethylase (EROD); tumor necrosis factor (TNF); vascular endothelial growth factor (VEGF); area under the curve (AUC); oral clearance (CL po ); human immunodeficiency virus (HIV); monoclonal antibodies (mAb); IL-2 receptor α (IL-2Rα); P-glycoprotein (P-gp); toll-like receptor (TLR); peak concentration (C max ); C-reactive protein (CRP)

Assessment of CYP3A‐mediated drug interaction via cytokine (IL‐6) elevation for mosunetuzumab using physiologically‐based pharmacokinetic modeling

“…9,10,[17][18][19][20][21][22] In a recent commentary, Chen et al summarized currently available data, compared relative suppressive potential of various cytokines in reference to IL-6, and reiterated the role of IL-6 and CYP3A enzyme suppression in causing potential clinical DDIs. 23 In our study, other than IL-6, mosunetuzumab does not meaningfully elevate the systemic level of other pro-inflammatory cytokines, such as IFN-, IL-2, and TNF. Therefore, it is necessary to assess potential CYP3A DDI risks caused by pharmacologically driven IL-6 elevation as a result of mosunetuzumab treatment in humans.…”

“…In a recent commentary, Chen et al. summarized currently available data, compared relative suppressive potential of various cytokines in reference to IL‐6, and reiterated the role of IL‐6 and CYP3A enzyme suppression in causing potential clinical DDIs 23 . In our study, other than IL‐6, mosunetuzumab does not meaningfully elevate the systemic level of other pro‐inflammatory cytokines, such as IFN‐, IL‐2, and TNF.…”

“…As summarized by Chen et al, comparing the observed and simulated effects of IL-6 elevation, the PBPK model predictions capture PK changes of CYP substrates in the presence of chronically and transiently elevated IL-6 reasonably well (i.e., predicted-to-observed ratios of mean AUC or C max < 2). 23 Our PBPK model built for mosunetuzumab with incorporation of in vitro IL-6 inhibition data was verified to predict clinical CYP3A DDI caused by both chronic and transient IL-6 elevation. The clinical DDI effect at transient IL-6 level beyond the verified IL-6 concentration range can be further confirmed once more clinical data become available.…”

“…Although dedicated clinical DDI studies have been broadly used for small molecule drug development, such studies have been limited for biologic-drug interactions due to the complexity study design, especially if DDI is caused indirectly through pharmacological mechanisms of action of the treatment agents. 23,35 A recent review by Jing et al revealed that of 150 approved TPs, 49 labels contained PK-related TP-DI information. More than half of the clinical DDI evaluations showed no interaction, 24 significant DDI (>2-fold) appears rare, and no dose adjustment has been recommended.…”

Role of Cytochrome P450 2C9 in COVID-19 Treatment: Current Status and Future Directions

“…CYP2C9, one of the most abundant CYP enzymes, metabolises 15–20% of drugs [ 16 ], some of which are extensively used by patients with COVID-19, for instance, warfarin [ 17 , 18 ], sulfonylureas [ 19 ], phenytoin [ 20 ] and non-steroidal anti-inflammatory drugs (NSAIDs) [ 21 ]. Further, studies have provided evidence that cytokines such as interleukin-6 (IL-6), tumour necrosis factor α (TNF-α) and interferon gamma (IFN-γ) suppress CYP2C9 expression [ 22 ].…”