Population Pharmacokinetic Modeling of Guselkumab, a Human IgG1λ Monoclonal Antibody Targeting IL‐23, in Patients with Moderate to Severe Plaque Psoriasis. (17th January 2018)

• Record Type: Journal Article
• Authors: Yao, Zhenling; Hu, Chuanpu; Zhu, Yaowei; Xu, Zhenhua; Randazzo, Bruce; Wasfi, Yasmine; Chen, Yang; Sharma, Amarnath; Zhou, Honghui
• Is Part Of: Journal of clinical pharmacology. Volume 58:Number 5(2018)
• Page Start: 613
• Page End: 627
• Publication Date: 2018-01-17
• Subjects: biologics -- clinical pharmacology -- dermatology -- modeling and simulation -- population pharmacokinetics; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Pharmacology, Clinical -- Periodicals; 615.1
• DOI: 10.1002/jcph.1063
• Languages: English
• ISSNs: 0091-2700

Abstract

Abstract: Psoriasis is a common inflammatory skin disorder that requires chronic treatment and is associated with multiple comorbidities. Guselkumab, a human immunoglobulin‐G1‐lambda monoclonal antibody, binds to interleukin‐23 with high specificity and affinity and is effective in treating moderate to severe plaque psoriasis. As part of the guselkumab psoriasis clinical trial program, using a confirmatory approach, a population pharmacokinetics (PopPK) model was established using 13 014 PK samples from 1454 guselkumab‐treated patients across 3 phase 2/3 trials. Observed serum guselkumab concentrations were adequately described by a 1‐compartment linear PK model with first‐order absorption and elimination. The final PK model was robust and stable, with apparent clearance (CL/F), apparent volume of distribution (V/F), and absorption rate constant (ka) estimates of 0.516 L/day, 13.5 L, and 1.11 day ‐1, respectively. A model‐derived elimination half‐life of 18.1 days indicated achievement of steady‐state serum guselkumab concentrations within 12–14 weeks. The primary covariate contributing to the observed PK variability was body weight, which accounted for only 28% (CL/F) and 32% (V/F) of the interindividual proportion of variance. Diabetes was identified to marginally reduce guselkumab exposure, owing to 12% higher CL/F in diabetic versus nondiabetic patients, but its contribution was not clinically relevant. None of the other covariates tested (eg, age, sex, ethnicity, immune response to guselkumab, or concomitant medications) had a clinically relevant effect on guselkumab exposure.