Upadacitinib pharmacokinetics and exposure‐response analyses of efficacy and safety in psoriatic arthritis patients – Analyses of phase III clinical trials

Muensterman, Elena Tomaselli; Engelhardt, Benjamin; Gopalakrishnan, Sathej; Anderson, J.; Mohamed, Mohamed‐Eslam F.

doi:10.1111/cts.13146

Cited by 24 publications

(17 citation statements)

References 34 publications

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“…Both UPA 15 and UPA 30 mg groups showed a better control in disease activity than the ADA control group, and the patients who switched from placebo to UPA showed similar disease improvements to patients firstly randomised to UPA. The total number of AEs and severe infective AEs were higher in the UPA 30 mg group (62,63). UPA pharmacokinetic was similar in PsA and RA patients, regardless of the concomitant use of csDMARDs (63).…”

Section: Mtx and Tnfimentioning

confidence: 89%

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Psoriatic arthritis: one year in review 2022

Cigolini

Fattorini

Gentileschi

et al. 2022

Clinical and Experimental Rheumatology

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Psoriatic arthritis is a systemic autoimmune disease, in which a characteristic heterogeneous inflammatory involvement of entheses and both peripheral and axial joints tends to be associated with different clinical features, in particular skin or nail psoriasis, but also inflammatory bowel diseases, or acute anterior uveitis. Patients with PsA are at higher risk of developing comorbidities, in particular metabolic syndrome, with a significant impact on their quality of life. Although the advanced knowledge in the pathogenetic mechanisms of PsA helped in developing an abundant therapeutical armamentarium, the available drugs might still show a suboptimal efficacy. However, the frontier of "personalised medicine" could promote further future improvement in the quality of care of patients. In this paper we reviewed the literature on PsA of 2020 and 2021 (Medline search of articles published from 1st January 2020 to 31th December 2021).

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Section: Mtx and Tnfimentioning

confidence: 89%

“…The total number of AEs and severe infective AEs were higher in the UPA 30 mg group (62,63). UPA pharmacokinetic was similar in PsA and RA patients, regardless of the concomitant use of csDMARDs (63). APR 30 mg x 2/day was significantly more effective in PsA patients with lower levels of disease activity.…”

Section: Mtx and Tnfimentioning

confidence: 90%

Psoriatic arthritis: one year in review 2022

Cigolini

Fattorini

Gentileschi

et al. 2022

Clinical and Experimental Rheumatology

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“…Upadacitinib ( Figure 66 ) is a JAK1 inhibitor that was approved to treat rheumatoid arthritis by the FDA in August 2019 [ 67 ]. It was also approved for the treatment of patients with psoriatic arthritis [ 195 ]. In 2022, upadacitinib was approved for treatment of atopic dermatitis [ 196 ].…”

Section: Introductionmentioning

confidence: 99%

“…Burmester et al [ 206 ] also evaluated the safety of upadacitinib in patients with psoriatic arthritis for up to 3 years, where the results revealed a safety profile similar to that observed in rheumatoid arthritis. Currently, upadacitinib has been approved by the FDA and EMA for the treatment of patients with active psoriatic arthritis [ 195 , 207 ].…”

Section: Introductionmentioning

confidence: 99%

A Comprehensive Overview of Globally Approved JAK Inhibitors

et al. 2022

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Janus kinase (JAK) is a family of cytoplasmic non-receptor tyrosine kinases that includes four members, namely JAK1, JAK2, JAK3, and TYK2. The JAKs transduce cytokine signaling through the JAK-STAT pathway, which regulates the transcription of several genes involved in inflammatory, immune, and cancer conditions. Targeting the JAK family kinases with small-molecule inhibitors has proved to be effective in the treatment of different types of diseases. In the current review, eleven of the JAK inhibitors that received approval for clinical use have been discussed. These drugs are abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, and upadacitinib. The aim of the current review was to provide an integrated overview of the chemical and pharmacological data of the globally approved JAK inhibitors. The synthetic routes of the eleven drugs were described. In addition, their inhibitory activities against different kinases and their pharmacological uses have also been explained. Moreover, their crystal structures with different kinases were summarized, with a primary focus on their binding modes and interactions. The proposed metabolic pathways and metabolites of these drugs were also illustrated. To sum up, the data in the current review could help in the design of new JAK inhibitors with potential therapeutic benefits in inflammatory and autoimmune diseases.

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“…Population pharmacokinetics and exposure-response analyses have been conducted for upadacitinib for several indications, such as RA [ 9 , 10 ], CD [ 11 ], PsA [ 12 ], and AD [ 13 ], which have informed optimal dosing for clinical benefit specific to each disease. The population pharmacokinetics and exposure-response analyses in this work characterized upadacitinib pharmacokinetics in patients with moderately to severely active UC across Phase 2b and 3 trials and evaluated the relationships between upadacitinib plasma exposures and key efficacy and safety endpoints using data from these trials during induction and maintenance treatment.…”

Section: Introductionmentioning

confidence: 99%

Upadacitinib Population Pharmacokinetics and Exposure-Response Relationships in Ulcerative Colitis Patients

et al. 2022

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Background and Objective Upadacitinib, an oral selective and reversible Janus kinase (JAK) inhibitor, showed favorable efficacy and safety in patients with moderate-to-severe ulcerative colitis (UC). The objective was to characterize upadacitinib pharmacokinetics in UC patients across Phase 2b and 3 trials and evaluate the relationships between upadacitinib plasma exposures and key efficacy or safety endpoints. Methods Population pharmacokinetics and exposure-response analyses were performed to characterize upadacitinib pharmacokinetics in UC patients and evaluate the relationships between plasma exposures and key efficacy or safety endpoints at the end of 8-week induction and 52-week maintenance periods. Data from 1234 UC patients from Phase 2 and 3 induction trials and 449 UC patients from a Phase 3 maintenance trial were used for these analyses. Additionally, data from patients with rheumatoid arthritis, atopic dermatitis, Crohn's disease, and healthy volunteers were used in the pharmacokinetics analysis. Quartile plots and logistic regression models were used to evaluate the exposure-response relationships across upadacitinib doses of 7.5-45 mg once daily (QD) for induction and 15-30 mg QD for maintenance. Results Upadacitinib plasma exposures were dose-proportional in UC patients across the evaluated dose range. Upadacitinib pharmacokinetics in UC were consistent between the induction and maintenance periods, and with other patient populations. Upadacitinib plasma exposures associated with the 45 mg QD induction dose maximized efficacy for Week 8 clinical and endoscopic endpoints. Plasma exposures associated with upadacitinib 30 mg maintenance dose provided additional incremental benefit compared to 15 mg QD for Week 52 key clinical and endoscopic endpoints. No trends were observed in the evaluated safety events with increasing plasma exposures at the end of induction or maintenance periods. Conclusion These analyses supported selection of upadacitinib UC induction and maintenance doses. Trial Registration Data from studies NCT02819635 and NCT03653026 were included in these analyses.

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Upadacitinib pharmacokinetics and exposure‐response analyses of efficacy and safety in psoriatic arthritis patients – Analyses of phase III clinical trials

Cited by 24 publications

References 34 publications

Psoriatic arthritis: one year in review 2022

Psoriatic arthritis: one year in review 2022

A Comprehensive Overview of Globally Approved JAK Inhibitors

Upadacitinib Population Pharmacokinetics and Exposure-Response Relationships in Ulcerative Colitis Patients

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