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

Abstract

Upadacitinib is an oral Janus kinase inhibitor approved for the treatment of rheumatoid arthritis (RA) and recently approved by the European Medicines Agency for the treatment of psoriatic arthritis (PsA). The efficacy and safety profile of upadacitinib in PsA have been established in the SELECT-PsA program in two global phase 3 studies which evaluated upadacitinib 15 and 30mg QD. The analyses described here characterized upadacitinib pharmacokinetics and exposure-response relationships for efficacy and safety endpoints using data from the SELECT-PsA studies. Upadacitinib pharmacokinetics in PsA patients were characterized through a Bayesian population analysis approach and were comparable to pharmacokinetics in RA patients. Exposure-response relationships for key efficacy and safety endpoints were characterized using data from 1,916 PsA patients. The percentage of patients achieving efficacy endpoints at Week 12 (ACR50 and ACR70), 16 and 24 (sIGA0/1) increased with increasing upadacitinib average plasma concentration over a dosing interval, while no clear exposure-response trend was observed for ACR20 at Week 12 or ACR20/50/70 at Week 24 within the range of plasma exposures evaluated in the phase 3 PsA studies. No clear trends for exposure-response relationships were identified for experiencing pneumonia, herpes zoster infection, hemoglobin <8g/dL, lymphopenia (Grade≥3), or neutropenia (Grade≥3) after 24 weeks of treatment. Shallow relationships with plasma exposures were observed for serious infections and hemoglobin decrease >2g/dL from baseline at Week 24. Based on exposure-response analyses, the upadacitinib 15mg QD regimen is predicted to achieve robust efficacy in PsA patients and to be associated with limited incidences of reductions in hemoglobin or occurrence of serious infections.

Psoriatic arthritis: one year in review 2022

“…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).…”

“…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.…”

A Comprehensive Overview of Globally Approved JAK Inhibitors

“…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 ].…”

“…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 ].…”

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

“…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.…”