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

Abstract

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.

Real-world effectiveness of upadacitinib in Crohn’s disease: a UK multicentre retrospective cohort study

“…This is not surprising given the highly refractory nature of the cohort and upadacitinib's increasing effectiveness in IBD with higher dosing. 11 Our data suggest that patients with Crohn's disease are less likely to do well with 15 mg dosing. This finding is also suggested in the real-world multicentre US study.…”

Population pharmacokinetics and exposure‐response analyses for efficacy and safety of upadacitinib in patients with axial spondyloarthritis

“…C exposure-response analyses for upadacitinib utilized model-estimated C avg , as the exposure metric, which is consistent with exposure-response analyses conducted in other patient populations. 27,33,34 The exposure-response analyses for efficacy in axSpA demonstrated a higher response for the upadacitinib 15 mg q.d. arm compared to placebo with no trend toward higher response rates with increasing upadacitinib plasma exposures within the 15 mg q.d.…”

Therapeutic Drug Monitoring for Biologic and Small-Molecule Therapies for Inflammatory Bowel Disease

“…For upadacitinib, it appears that induction dosing at 45 mg daily and maintenance dosing at 30 mg daily achieves maximal clinical and endoscopic healing [88,89]. The exposure-response appears to plateau above 45 mg daily during induction and over 30 mg daily during maintenance therapy.…”