S1860 Pharmacokinetics and Exposure-Response Relationships of Guselkumab Intravenous or Subcutaneous Induction in Participants With Ulcerative Colitis

Introduction: Guselkumab (GUS), a dual-acting IL-23p19 subunit inhibitor, is highly efficacious in participants (pts) with ulcerative colitis (UC) after intravenous (IV) or subcutaneous (SC) induction, followed by SC maintenance therapy. Here, we evaluated the pharmacokinetics (PK) and exposure-response (E-R) of IV and SC GUS induction. Methods: The GUS clinical development program in pts with moderately to severely active UC consisted of the phase 2b/3 QUASAR studies of IV induction (200 mg every 4 weeks [every 4 weeks] ×3) and SC maintenance (100 mg every 8 weeks [every 8 weeks] or 200 mg every 4 weeks) and the phase 3 ASTRO study of SC induction (400 mg every 4 weeks ×3) and SC maintenance (same as QUASAR). All studies had randomized, double-blind, placebo-controlled, parallel group designs. To compare GUS PK exposure after 200 mg IV vs 400 mg SC induction through week 12 (W12), individual post-hoc PK parameter values (estimated with the established QUASAR 2-compartment linear population PK [popPK] model with first-order absorption and elimination) and pt dosing information from QUASAR and ASTRO were used to simulate concentration-time profiles and calculate individual induction exposure metrics. Comparative graphical E-R analysis (QUASAR vs ASTRO) was conducted for key W12 efficacy outcomes (clinical remission, clinical response, endoscopic improvement, and histologic-endoscopic mucosal improvement) using the overall exposure during induction (Cave, week 0–12) and associated exposure quartiles from the combined study populations. Results: Consistent with model predictions, SC induction resulted in similar average concentrations (W0–W12), similar area under the concentration-time curves (W0–W12), lower peak concentrations (at W8), and higher trough concentrations (at W12) compared with the PK profile of IV induction. GUS steady-state concentration was reached by W24, and popPK model-based simulations showed that serum GUS concentrations were comparable by W24 after the same maintenance dose regimen, regardless of induction administration route. Key efficacy outcomes at W12 were comparable within the same GUS concentration quartiles following IV vs SC induction. Similar positive E-R trends were observed after IV or SC induction. Conclusion: Consistent average serum GUS concentrations and E-R patterns after IV and SC induction underscore the observed clinical efficacy and support the use of either induction administration route in UC patients.