Abstract
Introduction: Tofacitinib is an oral, small molecule JAK inhibitor that is being investigated for ulcerative colitis. A number of JAK inhibitors are being investigated in the treatment of inflammatory diseases, eg tofacitinib, baricitinib and filgotinib (GLPG0634), but it is unclear how their JAK-dependent cytokine inhibition profiles differ. Methods: We used an integrated modeling approach (using knowledge of in vitro whole cell JAK inhibition potencies and plasma pharmacokinetics [PK]) to understand cytokine inhibition profiles for clinically meaningful doses of JAK inhibitors. IC50 values for interferon (IFN)α, IFNγ, interleukin (IL)-6, IL-15, IL-21, IL-10, IL-27, IL-12, IL-23 and erythropoietin (EPO) signaling of tofacitinib, baricitinib, and filgotinib and metabolite were measured in total lymphocytes, CD34+ cells (EPO) and CD3+ cells (IL-6) in human whole blood by a flow cytometry-based assay. Human daily average plasma concentrations (Cav) for tofacitinib (5 mg BID; 68 nM), baricitinib (4 mg QD; 27 nM), and filgotinib (200 mg QD; 474 nM) and metabolite (7438 nM) were converted to unbound values with measured plasma fraction unbound (fu) values of 0.61, 0.59, 0.49 and 0.42, respectively. Whole blood IC50 values were converted to unbound values with measured blood/plasma ratios of 1.2, 1.3, 1.2 and 1.1, respectively, and fu values. Percentage levels of cytokine inhibition were determined at clinically meaningful doses. Results: Tofacitinib and baricitinib were overall more potent inhibitors than filgotinib and metabolite (data not shown). Combining potency with clinical PK showed a similar cytokine inhibition profile (Table), with some exceptions. The greater level of IL-6 inhibition noted with filgotinib and metabolite did not translate into greater C-reactive protein reductions vs tofacitinib1 and baricitinib.2 The minor difference in IL-15 inhibition between tofacitinib1 and baricitinib3 did not translate into a clinically meaningful difference in natural killer cells.Table: Table. Overall % cytokine inhibition in the context of clinical concentrations for various JAK inhibitorsConclusion: Cytokine inhibition for a number of JAK inhibitors was generally similar when efficacious doses are considered, with only minor differences in percentage cytokine inhibition, suggesting limited differentiation of these JAK inhibitors based on JAK pharmacology. Funded by Pfizer Inc.
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