Janus kinase inhibitors for the treatment of rheumatoid arthritis demonstrate similar profiles of in vitro cytokine receptor inhibition

Martin E. Dowty; Tsung H. Lin; Michael I. Jesson; Martin Hegen; David A. Martin; Vaibhav Katkade; Sujatha Menon; Jean‐Baptiste Telliez

doi:10.1002/prp2.537

journal article Open Access Nov 15, 2019

Janus kinase inhibitors for the treatment of rheumatoid arthritis demonstrate similar profiles of in vitro cytokine receptor inhibition

Martin E. Dowty

Tsung H. Lin Michael I. Jesson Martin Hegen David A. Martin Vaibhav Katkade Sujatha Menon Jean‐Baptiste Telliez

Pharmacology Research & Perspectives Vol. 7 No. 6 · Wiley

View at Publisher Save 10.1002/prp2.537

Abstract

AbstractJanus kinase (JAK) inhibitors have emerged as an effective class of therapies for various inflammatory diseases such as rheumatoid arthritis (RA). JAK inhibitors function intracellularly by modulating the catalytic activity of JAKs and disrupting the receptor‐mediated signaling of multiple cytokines and growth factors, including those with pro‐inflammatory activity. Understanding the inhibition profiles of different JAK inhibitors, based on the associated cytokine receptors and downstream inflammatory pathways affected, is important to identify the potential mechanisms for observed differences in efficacy and safety. This study applied an integrated modeling approach, using in vitro whole blood cytokine inhibition potencies and plasma pharmacokinetics, to determine JAK‐dependent cytokine receptor inhibition profiles, in the context of doses estimated to provide a similar clinical response in RA clinical trials. The calculated profiles of cytokine receptor inhibition for the JAK inhibitors tofacitinib, baricitinib, upadacitinib, and filgotinib and its metabolite, were generally similar when clinically efficacious doses for RA were considered. Only minor numerical differences in percentage cytokine receptor inhibition were observed, suggesting limited differentiation of these inhibitors based on JAK pharmacology, with each showing a differential selectivity for JAK1 heterodimer inhibition. Nevertheless, only robust clinical testing involving head‐to‐head studies will ultimately determine whether there are clinically meaningful differences between these JAK inhibitors. Furthermore, ongoing and future research into inhibitors with alternative JAK selectivity remains of clinical importance. Thus, all JAK inhibitors should be characterized via thorough preclinical, metabolic and pharmacological evaluation, adequate long‐term clinical data, and when available, real‐world experience.

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References

Details

Published: Nov 15, 2019
Vol/Issue: 7(6)
License: View

Authors

M

Martin E. Dowty

Pfizer Inc Cambridge MA USA

T

Tsung H. Lin

Pfizer Inc Cambridge MA USA

M

Michael I. Jesson

Pfizer Inc Cambridge MA USA

M

Martin Hegen

Pfizer Inc Cambridge MA USA

D

David A. Martin

Pfizer Inc Cambridge MA USA

V

Vaibhav Katkade

Pfizer Inc Collegeville PA USA

S

Sujatha Menon

Pfizer Inc Groton CT USA

J

Jean‐Baptiste Telliez

Pfizer Inc Cambridge MA USA

Funding

Pfizer

Cite This Article

Martin E. Dowty, Tsung H. Lin, Michael I. Jesson, et al. (2019). Janus kinase inhibitors for the treatment of rheumatoid arthritis demonstrate similar profiles of in vitro cytokine receptor inhibition. Pharmacology Research & Perspectives, 7(6). https://doi.org/10.1002/prp2.537

Janus kinase inhibitors for the treatment of rheumatoid arthritis demonstrate similar profiles of in vitro cytokine receptor inhibition

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