(S-077) Population Pharmacokinetic & Exposure-Response Analysis After Subcutaneous Administration of Guselkumab in Pediatric Participants with Moderate to Severe Plaque Psoriasis

Obinna Obianom – Johnson and Johnson Innovative Medicine; Wangda Zhou – Johnson and Johnson Innovative Medicine; Herta Crauwels – Johnson and Johnson Innovative Medicine; Vikash Sinha – Johnson and Johnson Innovative Medicine; An Vermeulen – Johnson and Johnson Innovative Medicine; Mahesh Samtani – Johnson and Johnson Innovative Medicine

Objectives: Guselkumab is a fully human IgG1λ mAb that binds to the p19 subunit of human interleukin (IL) -23 with high specificity and affinity. In turn, guselkumab blocks IL-23 binding to the cell surface IL-23 receptor, inhibiting downstream intracellular signaling. This analysis characterized the pharmacokinetics and exposure-response (E-R) of guselkumab in pediatric participants with moderate to severe psoriasis (PsO).

Methods: This population pharmacokinetic (PopPK) analysis was performed using 13,529 measurable serum guselkumab concentrations after subcutaneous administration of guselkumab (W0, W4 and Q8W thereafter) from 91 pediatric participants in a Phase 3 study (PROTOSTAR) with data up to Week 44, and 1,454 adult participants in one Phase 2 study (X-PLORE) and two Phase 3 studies (VOYAGE 1, VOYAGE 2) with data up to Week 52. The pediatric cohort consisted of 19 children (≥6 to < 12 years) and 72 adolescents (≥12 to < 18 years) and received guselkumab dosed at 1.3 mg/kg for body weight < 70 kg or 100 mg for body weight ≥70 kg. All adult participants received a guselkumab dose of 100 mg.
The PopPK model was developed by updating a previous PopPK model for adults, by fixing the allometric exponents of body weight on CL/F and V/F to 0.75 and 1.0, respectively. The updated model parameters were subsequently re-estimated using adult data from X-PLORE, VOYAGE 1 and VOYAGE 2. External evaluation was carried out using pediatric data from PROTOSTAR. Simulations were conducted to assess the comparability of pediatric and adult exposures for the doses studied. Graphical E-R analysis was performed for the pediatric cohort.

Results: The observed concentration-time data for guselkumab in pediatric participants with PsO were well described by an updated 1-compartment linear PK model with first-order absorption and first-order elimination developed using the adult data. All parameters were estimated with good precision, with RSEs less than 20%. The typical population estimates for CL/F and V/F were 0.516 L/day and 13.5 L, respectively. The model-derived elimination half-life was approximately 18 days. Baseline body weight was the primary covariate contributing to the observed PK variability of guselkumab. This was accounted for in the pediatric dose regimen. Comorbid diabetes and race had a statistically significant but not clinically relevant effect (18% and 7%, respectively) on guselkumab CL/F, and were retained in the model as covariates. Simulation results confirmed that with the studied pediatric dosing regimen in PROTOSTAR, pediatric participants attained similar PK exposures as the adult participants. Graphical E-R assessment for the primary endpoints (IGA 0/1, PASI 75, and PASI 90 response rates at Week 16) in pediatric participants showed no apparent E-R trend across quartiles of Cweek16 and AUCweek0-16.

Conclusions: An updated adult PopPK model was used to characterize the PK of guselkumab following subcutaneous administration in pediatric participants with moderate to severe PsO. Results indicated that the updated PopPK model is robust and predicts guselkumab PK exposures across the full body weight range for both pediatric and adult age groups. Pediatric exposures were shown to be comparable to adult exposures.

Citations: [1] Yao et al. Population Pharmacokinetic Modeling of Guselkumab, a Human IgG1λ Monoclonal Antibody Targeting IL-23, in Patients with Moderate to Severe Plaque Psoriasis. J Clin Pharmacol . 2018 May;58(5):613-627.

Keywords: guselkumab, pso, tremfya, pediatrics