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

Abstract

Janus 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.

Therapeutic Maintenance of Baricitinib and Tofacitinib in Real Life

“…JAKis reduce inflammation by modulating the intracellular activity of JAKs and disrupting the signaling of multiple pro-inflammatory cytokines. In France in 2017, two molecules became available in current practice: baricitinib and tofacitinib; these can be prescribed as second-line therapy after conventional synthetic disease-modifying antirheumatic drug (csDMARD) failure [ 2 , 3 , 4 , 5 ].…”

Demonstration of In Vitro to In Vivo Translation of a TYK2 Inhibitor That Shows Cross Species Potency Differences

“…Anti-pSTAT4-AlexaFluor647 was used for IL-12-stimulated samples. Anti-pSTAT5-AlexaFluor647 was used for IL-15 stimulated samples 21,27 .…”

Baricitinib: New Pharmacotherapy Options for Rheumatoid Arthritis and Other Immune-Mediated Inflammatory Rheumatic Diseases

“…Что касается БАРИ, то in vitro этот препарат (как и другие ингибиторы JAK) в большей или меньшей степени блокирует сигнализацию широкого спектра цитокинов, независимо от типа JAK [102]: JAK1/3 (CD4+ Т-клетки, моноциты) -ИЛ2, ИЛ4, ИЛ15, ИЛ21, JAK2/2 или JAK2/TYK2 (моноциты) -ИЛ3, гранулоцитарный колониестимулирующий фактор (Г-КСФ), ГМ-КСФ и JAK1/JAK2/TYK2 (CD4+ Т-клетки, моноциты) -ИЛ6, ИЛ10, интерферон γ (ИФНγ), ИФНα. Сходные данные получены в другом исследовании [103], в котором сравнивалась способность БАРИ, ТОФА и двух селективных ингибиторов JAK1 -упадацитиниба и филготиниба -блокировать in vitro сигнализацию цитокинов в CD4+ Т-клетках, CD3+ Т-клетках, лимфоцитах и гранулоцитах. Наряду с перечисленными выше «мишенями» выявлено блокирование ИЛ13 и ИЛ27 (JAK1/JAK2, JAK1/TYK2), ИЛ7 (JAK1/JAK3), ИЛ12 и ИЛ 23 (JAK2/TYK2), эритропоэтина (JAK2/JAK2).…”