M. Dowty, T. Lin, L. Wang
Jun 1, 2014
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Influential Citations
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Quality indicators
Journal
Annals of the Rheumatic Diseases
Abstract
Background A number of Janus kinase (JAK) inhibitors are being actively investigated for treatment of rheumatoid arthritis (RA), including tofacitinib, baricitinib, filgotinib (GLPG0634), and decernotinib (VX-509). However, it is unclear how these drugs may differentiate from each other in the clinic based on their profiles of JAK dependent cytokine inhibition. Objectives The aim of this work was to provide an integrated modelling approach using knowledge of both whole cell JAK inhibition potencies and plasma pharmacokinetics to better understand profiles of cytokine inhibition for clinical JAK inhibitors in the context of clinically meaningful doses. Methods IC50 values for IFNα, IFNγ, IL-6, IL-15, IL-21, IL-10, IL-27, IL-12, IL-23 and erythropoietin (EPO) signalling of tofacitinib, baricitinib, filgotinib, and decernotinib were measured in total lymphocytes, CD34+ cells (EPO) and CD3+ cells (IL-6) in human whole blood by a flow cytometry-based assay, quantifying the phosphorylation state of various STAT proteins. Human daily average plasma concentrations (Cav) were used as reported or predicted for tofacitinib (5 mg BID; 68 nM), baricitinib (4 mg QD; 32 nM), and filgotinib (200 mg QD; 527 nM). Confidence in the prediction of decernotinib pharmacokinetics was considered low because of high in-vitro metabolic instability and was not assessed further. Percent levels of cytokine inhibition (ICxx=100*Cav/(IC50 + Cav)) were determined at clinically meaningful doses. Results Each JAK inhibitor showed a relatively similar profile of cytokine inhibition versus type I and II interferons (IFNα, IFNγ), the common γ chain cytokines (IL-15, IL-21), and IL-6 and IL-27 (Fig. 1). Each also showed some decrease in potency for IL-10, IL-12 and 23, and EPO. Comparing between JAK inhibitors, tofacitinib and baricitinib were overall more potent inhibitors than decernotinib and filgotinib. Clinical pharmacokinetics of tofacitinib, baricitinib, and filgotinib were available and used to further compare predicted cytokine profiles of inhibition in patients with RA. The profile of cytokine inhibition for each JAK inhibitor was strikingly similar at clinically meaningful doses (Fig. 1). While the pharmacokinetics were unavailable for decernotinib, the clinical dose ranges being explored are consistent with filgotinib which showed similar in-vitro inhibitory potencies. Figure 1. In vitro whole blood JAK inhibitory potencies (left) and overall cytokine inhibition in the context of clinical concentrations (right) for various JAK inhibitors. Conclusions These analyses illustrate the importance of studying a broad range of JAK pairing potencies and clinical concentrations when comparing JAK inhibitor compounds. Clinical profiles of cytokine inhibition for a number of JAK inhibitors in RA are strikingly similar when efficacious doses are considered, suggesting limited potential for differentiation of these JAK inhibitors based on JAK pharmacology. Disclosure of Interest M. Dowty Employee of: Pfizer Inc, T. Lin Employee of: Pfizer Inc, L. Wang Employee of: Pfizer Inc, J. Jussif Employee of: Pfizer Inc, B. Juba Employee of: Pfizer Inc, L. Li Employee of: Pfizer Inc, E. Moy Employee of: Pfizer Inc, J.-B. Telliez Employee of: Pfizer Inc DOI 10.1136/annrheumdis-2014-eular.2490