Pharmacokinetic/Pharmacodynamic Analysis of Guselkumab for Treatment of Palmoplantar Pustulosis: Clinical Implications of Guselkumab Dose, Disease Severity and Smoking in Japanese Patients.

Abstract

Guselkumab is a human IgG1λ monoclonal antibody that has been approved for treatment of multiple immunological diseases including palmoplantar pustulosis (PPP) in Japan. The efficacy of guselkumab in reducing disease severity as compared with placebo has been demonstrated in phase 2 and 3 clinical studies. In some patients assigned to the placebo treatment, worsening of PPP Area and Severity Index (PPPASI) score was noted. Most of these patients were smokers, raising a possibility of an association of smoking with the disease progression. To understand the clinical implications of guselkumab dose, baseline disease severity and smoking on the treatment effect and describe the longitudinal relationship between guselkumab exposure and the PPPASI score, a PK/PD modeling analysis was conducted using the pooled data from one phase 2 and one phase 3 study. Data from 207 Japanese patients (77% women and 60% smokers) with a median PPPASI score of 24.6 were included in the analysis. The observed treatment efficacy (the PPPASI score reduction) appeared to be similar at the current approved dose (100) mg and the higher dose (200 mg). Greater extent of the PPPASI score reduction (in absolute points) is expected in patients with higher baseline PPPASI score (severe disease). However, the higher baseline did not translate to larger magnitude of the change from baseline (in percentage) in the PPPASI score. Incorporating a linear disease progression effect in the model significantly decreased the NONMEM objective function value (p<0.001). Smoking status appeared tobe related to disease worsening in some patients, but the covariate did not reach statistical significance in the model. This article is protected by copyright. All rights reserved.