Abstract：
:Guselkumab, a human IgG1 monoclonal antibody that blocks interleukin-23, has been evaluated in one Phase 2 and two Phase 3 trials in patients with moderate-to-severe psoriasis, in which disease severity was assessed using Psoriasis Area and Severity Index (PASI) and Investigator's Global Assessment (IGA) scores. Through the application of landmark and longitudinal exposure-response (E-R) modeling analyses, we sought to predict the guselkumab dose-response (D-R) relationship using data from 1459 patients who participated in these trials. A recently developed novel latent-variable Type I Indirect Response joint model was applied to PASI75/90/100 and IGA response thresholds, with placebo effect empirically modeled. An effect of body weight on E-R, independent of pharmacokinetics, was identified. Thorough landmark analyses also were implemented using the same dataset. The E-R models were combined with a population pharmacokinetic model to generate D-R predictions. The relative merits of longitudinal and landmark analysis also are discussed. The results provide a comprehensive and robust evaluation of the D-R relationship.
journal_name
J Pharmacokinet Pharmacodynjournal_title
Journal of pharmacokinetics and pharmacodynamicsauthors
Hu C,Yao Z,Chen Y,Randazzo B,Zhang L,Xu Z,Sharma A,Zhou Hdoi
10.1007/s10928-018-9581-1subject
Has Abstractpub_date
2018-08-01 00:00:00pages
523-535issue
4eissn
1567-567Xissn
1573-8744pii
10.1007/s10928-018-9581-1journal_volume
45pub_type
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