Associate director Johnson & Johnson Innovative Medicine, United States
Objectives: Guselkumab (Tremfya®) is a human monoclonal antibody that binds to the p19 protein subunit of interleukin (IL)-23, inhibiting IL-23 specific intracellular signaling and subsequent activation and cytokine production. The purpose of the population pharmacokinetic (PopPK) analysis was to support regulatory submissions of guselkumab intravenous (IV) or subcutaneous (SC) induction dosing followed by SC maintenance dosing for the treatment of moderately to severely active Crohn’s disease (CD).
Methods: The PopPK analysis was performed using 10,632 serum concentration-time data from 1,009 participants from a Phase 2 dose-ranging study (GALAXI 1) and 3 Phase 3 studies (GALAXI 2, GALAXI 3, and GRAVITI). Three IV induction dose regimens of 200, 600, or 1200 mg every 4 weeks (q4w) ×3 doses were evaluated in GALAXI 1, while the lowest induction dose regimen (200 mg q4w ×3 doses) was evaluated in the confirmatory Phase 3 GALAXI studies (GALAXI 2 and GALAXI 3). A single SC induction dose regimen of 400 mg q4w ×3 doses was evaluated in GRAVITI. Two SC maintenance dose regimens: 100 mg every 8 weeks (q8w) and 200 mg q4w, were evaluated in both GALAXI (database lock at Week 48) and GRAVITI (database lock at Week 24). Covariate assessment focused primarily on the effects on clearance (CL), except for body weight which was also assessed on the volumes of distribution. Simulations were conducted to compare guselkumab PK concentration time profiles and exposure metrics following the guselkumab dose regimen in the GALAXI studies versus the GRAVITI studies.
Results: Serum concentration-time data of guselkumab were adequately described by a 2-compartment linear PK model with first-order absorption after SC administration and first-order elimination. The typical PopPK parameter estimates were 0.304 L/day for CL, 0.319 L/day for Q, 3.59 L for Vc and 2.53 L for Vp. The typical values of ka and SC bioavailability were 0.107 day-1 and 53.5%, respectively. T1/2 was estimated as 16.8 days. Of the covariates evaluated, higher body weight, lower serum albumin, higher CRP levels, and prior failure to biologics were associated with higher CL. Dose adjustment is not warranted based on the magnitude of the effect of these covariates on guselkumab exposure metrics. The 400 mg SC q4w induction dose regimen in GRAVITI resulted in lower Cmax, similar Cave,week0-12, and numerically higher Ctrough,week12 compared with the corresponding exposure metrics following the 200 mg IV q4w induction regimen in GALAXI. PopPK model-based simulations showed that the impact of different routes of administration (ie, IV versus SC) during the induction period was no longer noticeable by Week 24 across both guselkumab maintenance SC dose regimens.
Conclusions: A PopPK model was developed for guselkumab in participants with moderately to severely active CD which successfully characterized the impact of covariates and different routes of administration employed during the induction period.
