P341 Pharmacokinetics and exposure-response analyses of upadacitinib in patients with moderate to severe ulcerative colitis – Analyses of induction and maintenance clinical trials
Ponce-Bobadilla, A.V.(1);Stodtmann, S.(1);Eckert, D.(1);Zhou, W.(2);Liu, W.(2);Mohamed, M.E.(2);
(1)AbbVie Deutschland GmbH & Co. KG, Research and Development, Ludwigshafen, Germany;(2)AbbVie, Research and Development, North Chicago- IL, United States;
Background
Upadacitinib (UPA), an oral selective and reversible JAK1 inhibitor, showed favorable efficacy and safety profile in Phase 2b and 3 studies in subjects with moderate to severe ulcerative colitis (UC). Population pharmacokinetics and exposure-response analyses were performed to characterize the relationships between UPA plasma exposures and key efficacy and safety endpoints using data from these studies.
Methods
The pharmacokinetics (PK), efficacy, and safety of UPA for induction and maintenance treatment in UC were evaluated in a Phase 2b induction, two replicate Phase 3 induction, and a Phase 3 maintenance clinical trials. UPA PK was characterized using data from 978 UC patients. UPA exposure-response relationships for key efficacy and safety endpoints at the end of induction and maintenance periods were characterized using data from 1,234 and 449 UC patients, respectively. Quartile plots and logistic regression models were used to evaluate the exposure-response relationships across UPA doses of 7.5 mg to 45 mg once daily (QD) for induction and 15 mg to 30 mg QD for maintenance.
Results
UPA PK in UC patients was consistent with other patient populations and between the induction and maintenance periods. The percentage of subjects achieving clinical and endoscopic efficacy endpoints at the end of the induction increased with increasing UPA average plasma concentration (Cavg), and became mostly flat at Cavg values approximately equivalent to the 45 mg QD (Figure 1). For maintenance treatment, there was a trend for increasing the percentage of subjects achieving clinical remission, steroid-free remission, endoscopic improvement, and histo-endoscopic mucosal improvement within the range of UPA plasma exposures evaluated. Exposures associated with UPA 30 mg QD were estimated to provide a 8% to 10% increase in the percentage of subjects achieving these endpoints compared to 15 mg QD (Figure 2). There was no trend for exposure-response relationships within the range of evaluated UPA exposures for any of the evaluated safety endpoints (>2 g/dL decrease in hemoglobin and >2 g/dL decrease in hemoglobin and < lower limit for normal, hemoglobin < 8 g/dL, lymphopenia ≥ Grade 3, neutropenia ≥ Grade 3, Herpes Zoster infection, serious infections, and pneumonia) at the end of induction or maintenance periods.
Conclusion
UPA plasma exposures associated with the 45 mg QD induction dose maximized efficacy for clinical and endoscopic endpoints at Week 8. Plasma exposures associated with UPA 30 mg maintenance dose provide additional incremental benefit compared to 15 mg QD. No trends were observed for increase in the evaluated safety events with increasing UPA plasma exposures at the end of induction or maintenance periods.