(M-018) Population Pharmacokinetic Assessment of Guselkumab in Adults with Moderately to Severely Active Ulcerative Colitis

Jafar Sadik Shaik, PhD – Associate Director, Johnson and Johnson Innovative Medicine; Yu Kyoung Cho, PhD – Sr. Scientist, Johnson and Johnson Innovative Medicine; Yuan Xiong, PhD – Director, Johnson and Johnson Innovative Medicine; Jie Shao, PhD – Sr. Scientist, Johnson and Johnson Innovative Medicine; Zhenhua Xu, PhD – Sr. Director, Johnson and Johnson Innovative Medicine; An Vermeulen, PhD – Sr. Director, Johnson and Johnson Innovative Medicine; Mahesh Samtani, PhD – Sr. Director, Johnson and Johnson Innovative Medicine

Objectives: Guselkumab, an IL-23p19 subunit inhibitor, is approved for the treatment of adults with moderate to severe plaque psoriasis and active PsA in countries/territories globally. The population pharmacokinetic (PopPK) analysis was performed using pharmacokinetic (PK) data of guselkumab in adult participants with moderately to severely active ulcerative colitis (UC) with an objective to characterize the PK of guselkumab following intravenous (IV) and subcutaneous (SC) administration in this patient population.

Methods: The PopPK analysis was performed using pooled PK data from 859 adult participants with UC from a Phase 2b induction dose-ranging study, a Phase 3 induction study, and a Phase 3 maintenance study. Across the three clinical studies, guselkumab doses of 200 mg and 400 mg q4w were administered intravenously during the first 12-week induction period, while doses of 100 mg q8w and 200 mg q4w were administered subcutaneously in the maintenance phase.
Potential covariates on guselkumab PK were evaluated on the clearance (CL) though body weight was also evaluated on the volumes of distribution. The final PopPK model was used to simulate post hoc exposures and construct forest plots for assessing the effect of covariates during the induction phase (C_{trough, week12} and C_{average, week0-12}) with a fixed dose regimen of 200 mg IV q4w × 3 and during the maintenance phase (C_{trough, week44} and C_{average, week40-44}) with a fixed dose regimen of 200 mg SC q4w.

Results: Serum guselkumab concentration-time data from the three studies were adequately described by a 2-compartment PK model with first-order absorption after SC dosing and linear elimination. The typical values of CL, Q, V₂, and V₃ in participants with a body weight of 70 kg were 0.312 L/day, 0.298 L/day, 3.38 L, and 2.58 L, respectively. The typical values of ka and F1 were 0.123 day^-1 and 58.8%, respectively. The terminal elimination half-life for a typical participant was 16.5 days. Body weight, baseline serum albumin, baseline CRP, age, sex, and prior biologic failure status were found to be statistically significant covariates for the PK of guselkumab. Furthermore, forest plots for C_trough or C_average during both induction and maintenance periods were generated to evaluate effect sizes from relevant patient characteristics. No clinically relevant impact was identified for any potential covariates, as either the point estimates or the upper/lower end of their associated 90% CI fell within the range of 0.8 to 1.25.

Conclusions: A final PopPK model of guselkumab in adult participants with moderately to severely active UC was developed. All parameters were well estimated, and the covariate effects were physiologically reasonable and consistent with previous knowledge and/or findings from guselkumab PK in other indications. Forest plots constructed using simulated exposure metrics based on the final PopPK model showed that dose adjustment based on covariate effects is not warranted.

Citations: No citation