Background: The Janus kinase inhibitor (JAKI) upadacitinib is an orally administered small molecule that selectively inhibits the Janus Kinase 1 (JAK1) and is indicated for the treatment of rheumatological and dermatological disorders as well as inflammatory bowel diseases (IBDs). Dose-response relationship and exposition-dependent adverse drug reactions (ADRs) were reported in several disease areas, including rheumatological disorders [1–5]. However, upadacitinib is prescribed according to a “one-size fits all” approach, without accounting for between-subject variability associated with genetic, environmental and disease conditions.

Objectives: We hypothesized that patients taking upadacitinib benefit from Therapeutic Drug Monitoring (TDM) to improve safety and efficacy. This prospective observational study aims to characterize the pharmacokinetic (PK) profile of upadacitinib in a real-life patient population along with its variability and factors responsible for it such as patient characteristics, drug-drug interactions, and pathophysiological status using a population pharmacokinetic (popPK) modeling approach. Moreover, we aim to explore the feasibility and utility of TDM-guided upadacitinib individual dosing administration in various inflammatory conditions.

Methods: The study was conducted in three Swiss hospital centers. Adult patients (≥ 18-year-old) receiving upadacitinib were enrolled in the study either for sparse samples collected at unselected times after the last drug intake during routine medical visits, or for a detailed PK sub-study investigation (serial blood samples over 8h). The time of the last drug intakes preceding each sampling and of blood samplings themselves were precisely recorded. Specific information was also captured at each sampling time: anthropometric and demographic characteristics (year of birth, sex, body weight, height, body mass index), chemistry laboratory parameters, dose, date of the first dose, diagnosis, comorbidities, list of co-medications, and any information on organ dysfunction. Pharmacodynamic (PD) data related to efficacy was collected through clinical outcome scores, while ADRs were recorded according to the Common Terminology Criteria for Adverse Events (CTCAE, v5.0) classifications. Preliminary popPK analysis was performed on currently available data using non-linear mixed effect modelling software. The model was used to predict individual upadacitinib dose-normalized trough level (C _min ) and clearance in different patient populations.

Results: Until December 2024, a total of 157 plasma concentrations of upadacitinib were analyzed in 47 patients with axial spondylarthritis (n = 11), psoriatic arthritis (n = 6), rheumatoid arthritis (n = 3), Crohn’s disease (n = 12), ulcerative colitis (n = 11), atopic dermatitis (n = 6), and other autoimmune disorders (n = 8) such as hidradenitis suppurativa, osteitis, and psoriasis. The detailed PK sub-study and the sparse sampling investigation included 11 and 36 patients respectively. Subjects were predominantly female (68%), with a median age of 47 years (range: 19-87 years) and a median BMI of 25.6 kg/m ² (range: 18.8-43.1 kg/m ² ). Dosages of upadacitinib ranged from 15 mg to 45 mg per day, with most patients receiving 15 mg once daily. In total, 10 patients (21%) reported insufficient responses, while ADRs were observed in 13 participants (28%). The most common ADRs were dermatological disorders, primarily acne, reported in 21% of patients (n = 10), followed by elevated cholesterol and hypertriglyceridemia (8%, n = 4), and headache (8%, n = 4). A one-compartment model with zero order absorption and linear elimination best described available upadacitinib data. Median (range) C _min was lower in patients with IBDs [0.12 (0.00-0.35) ng/mL/mg)] compared to those with rheumatological disorders [0.20 (0.01-0.62) ng/mL/mg] with a trend showing higher clearance of 58 L/h versus 42 L/h, respectively.

Conclusion: Our findings reveal that patients with IBDs may eliminate upadacitinib faster than those with rheumatological disorders. To our knowledge, this project is the first large-scale study to investigate the PK/PD profile of upadacitinib and characterize its variability in a “real-world” population. By exploring the relationship between drug exposure, treatment response and tolerability, it aims to provide critical insights for precise dose optimisation, addressing dose-dependent efficacy and tolerability issues.

REFERENCES: [1] McInnes IB, Kato K, Magrey M, Merola JF, Kishimoto M, Haaland D, et al. Efficacy and Safety of Upadacitinib in Patients with Psoriatic Arthritis: 2-Year Results from the Phase 3 SELECT-PsA 1 Study. Rheumatology and Therapy. 2023;10(1):275-92.

[2] McInnes IB, Anderson JK, Magrey M, Merola JF, Liu Y, Kishimoto M, et al. Trial of Upadacitinib and Adalimumab for Psoriatic Arthritis. N Engl J Med. 2021;384(13):1227-39.

[3] Fleischmann R, Curtis JR, Charles-Schoeman C, Mysler E, Yamaoka K, Richez C, et al. Safety profile of upadacitinib in patients at risk of cardiovascular disease: integrated post hoc analysis of the SELECT phase III rheumatoid arthritis clinical programme. Ann Rheum Dis. 2023;82(9):1130.

[4] Fleischmann R, Meerwein S, Charles-Schoeman C, Combe B, Hall S, Khan N, et al. Efficacy and safety of upadacitinib in patients with rheumatoid arthritis and inadequate response or intolerance to biological treatments: results through 5 years from the SELECT-BEYOND study. RMD Open. 2024;10(3):e003918.

[5] Cohen SB, van Vollenhoven RF, Winthrop KL, Zerbini CAF, Tanaka Y, Bessette L, et al. Safety profile of upadacitinib in rheumatoid arthritis: integrated analysis from the SELECT phase III clinical programme. Ann Rheum Dis. 2021;80(3):304-11.

Acknowledgements: The authors would like to thank all the patients who participated in the study, as well as the physicians and study nurses for their invaluable assistance and implication to blood sample collection and patient recruitment: Diana Dan; Eva Benillouche; Thomas Hügle; Dagmar Simon; Erne May Jane; Christian Mottet; Delaviz Golshayan; and David Haefliger. This research is supported by the Swiss National Science Foundation, grant number N° 320030_227827.

Disclosure of Interests: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.