Dataset Information

Comparison of baricitinib, upadacitinib, and tofacitinib mediated regulation of cytokine signaling in human leukocyte subpopulations.

ABSTRACT:

Background

The in vitro pharmacology of baricitinib, upadacitinib, and tofacitinib was evaluated to understand differences among these JAK inhibitors (JAKis) at the cellular level.

Methods

Peripheral blood mononuclear cells from healthy donors were incubated with different JAKis, levels of phosphorylated signal transducer and activator of transcription (pSTAT) were measured following cytokine stimulation, and half maximum inhibitory concentration (IC₅₀) values were calculated in phenotypically gated leukocyte subpopulations. Therapeutic dose relevance of the in vitro analysis was assessed using calculated mean concentration-time profiles over 24?h obtained from JAKi-treated subjects. Time above IC₅₀ and average daily percent inhibition of pSTAT formation were calculated for each JAKi, cytokine, and cell type.

Results

Distinct JAKis displayed different in vitro pharmacologic profiles. For example, tofacitinib and upadacitinib were the most potent inhibitors of the JAK1/3-dependent cytokines tested (interleukin [IL]-2, IL-4, IL-15, and IL-21) with lower IC₅₀ values and increased time above IC₅₀ translating to a greater overall inhibition of STAT signaling during the dosing interval. All JAKis tested inhibited JAK1/2-dependent cytokines (e.g., IL-6 and interferon [IFN]-?), the JAK1/tyrosine kinase 2 (TYK2)-dependent cytokines IL-10 and IFN-?, the JAK2/2-dependent cytokines IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), and the JAK2/TYK2-dependent cytokine granulocyte colony-stimulating factor (G-CSF), but often to significantly differing degrees.

Conclusions

Different JAKis modulated distinct cytokine pathways to varying degrees, and no agent potently or continuously inhibited an individual cytokine signaling pathway throughout the dosing interval. Notably, baricitinib inhibited JAK1/3 signaling to a lesser extent than upadacitinib and tofacitinib, while upadacitinib, baricitinib, and tofacitinib inhibited the signaling of JAK2/2-dependent cytokines, including GM-CSF and IL-3, as well as the signaling of the JAK2/TYK2-dependent cytokine G-CSF.

SUBMITTER: McInnes IB

PROVIDER: S-EPMC6679539 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

Comparison of baricitinib, upadacitinib, and tofacitinib mediated regulation of cytokine signaling in human leukocyte subpopulations.

McInnes Iain B IB Byers Nicole L NL Higgs Richard E RE Lee Jonathan J Macias William L WL Na Songqing S Ortmann Robert A RA Rocha Guilherme G Rooney Terence P TP Wehrman Thomas T Zhang Xin X Zuckerman Steven H SH Taylor Peter C PC

Arthritis research & therapy 20190802 1

<h4>Background</h4>The in vitro pharmacology of baricitinib, upadacitinib, and tofacitinib was evaluated to understand differences among these JAK inhibitors (JAKis) at the cellular level.<h4>Methods</h4>Peripheral blood mononuclear cells from healthy donors were incubated with different JAKis, levels of phosphorylated signal transducer and activator of transcription (pSTAT) were measured following cytokine stimulation, and half maximum inhibitory concentration (IC<sub>50</sub>) values were calc ...[more]

PMID: 31375130

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Project description:IntroductionUpadacitinib and tofacitinib are Janus kinase inhibitors approved for moderate-to-severe rheumatoid arthritis (RA). In the absence of head-to-head trials comparing their effectiveness, this study assessed the efficacy of upadacitinib 15 mg once-daily monotherapy/combination therapy against tofacitinib 5 mg twice-daily combination therapy among patients with RA using matching-adjusted indirect comparisons (MAICs).MethodsThe first of two MAICs used individual patient data (IPD) from the 14-week SELECT-MONOTHERAPY trial (upadacitinib [n = 217] vs. methotrexate [n = 216]) and published data from the ORAL Standard trial (tofacitinib + methotrexate [n = 204] vs. methotrexate [n = 108]). The second MAIC used IPD from the 26-week SELECT-COMPARE trial (upadacitinib + methotrexate [n = 647] vs. adalimumab + methotrexate [n = 324]) and published data from ORAL Strategy (tofacitinib + methotrexate [n = 376] vs. adalimumab + methotrexate [n = 386]). Data from patients in the upadacitinib trials were re-weighted based on age, sex, race, swollen joint count 66/28, tender joint count 68/28, C-reactive protein (CRP), and patients' global assessments to match the patient characteristics in tofacitinib trials. After matching, ACR20/50/70 and clinical remission (SDAI[CRP] ≤ 3.3, CDAI ≤ 2.8, DAS28-ESR/CRP < 2.6) were compared for upadacitinib vs. tofacitinib + methotrexate at month 3 and upadacitinib + methotrexate vs. tofacitinib + methotrexate at months 3 and 6 using Wald tests.ResultsAt month 3, upadacitinib monotherapy patients experienced significantly larger improvement in ACR70 compared to tofacitinib + methotrexate (mean difference in difference [DID]: 9.9%; p = 0.019), while upadacitinib + methotrexate was associated with higher ACR50 compared to tofacitinib + methotrexate (DID: 12.9%; p = 0.011). At month 6, upadacitinib + methotrexate patients experienced significantly larger improvement in SDAI/CDAI/DAS28-ESR clinical remission compared to tofacitinib + methotrexate, with DIDs of 9.1% (p = 0.011), 7.5% (p = 0.038), and 11.3% (p = 0.002), respectively.ConclusionsCompared to tofacitinib combination therapy, treatment with upadacitinib monotherapy and combination therapy were associated with improved outcomes at 3/6 months (monotherapy: ACR70; combination: ACR50, SDAI, CDAI, and DAS28-ESR remission).

Dataset Information

Comparison of baricitinib, upadacitinib, and tofacitinib mediated regulation of cytokine signaling in human leukocyte subpopulations.

Background

Methods

Results

Conclusions

Publications

Comparison of baricitinib, upadacitinib, and tofacitinib mediated regulation of cytokine signaling in human leukocyte subpopulations.

Similar Datasets

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