title: Population-based exposure-efficacy modeling of ustekinumab in patients with moderate to severe plaque psoriasis.
abstract: Ustekinumab, a human immunoglobulin G1 kappa (IgG1k) monoclonal antibody that binds with high affinity to human interleukin-12 and interleukin-23, has demonstrated efficacy in patients with psoriasis. The objective of this study was to perform exposure-response modeling to increase the understanding of reduction in disease severity following treatment with ustekinumab in patients with moderate to severe psoriasis who participate in two phase III studies (PHOENIX 1 and PHOENIX 2). Patients were randomly assigned to receive ustekinumab 45 mg or 90 mg (n = 1312; 11,624 Psoriasis Area and Severity Index [PASI] scores) or placebo (n = 665; 3278 PASI scores). Disease severity was assessed using PASI scores. A population mechanism-based exposure-response model of ustekinumab using NONMEM was developed using serum ustekinumab concentrations and PASI scores. The pharmacodynamic response effect was the reduction in PASI score. The placebo effect, although minor, was also integrated into the model. None of the covariate factors evaluated (eg, demographics, baseline disease characteristics, comorbidities) significantly contributed to the between-subject variability in the pharmacodynamic parameters. The developed exposure-response model can serve as a basis to support future alternative dosing regimens for ustekinumab in patients with moderate to severe plaque psoriasis. A robust exposure-response relationship has been confirmed for ustekinumab in psoriasis.
authors.affiliation: Pharmacokinetics, Modeling & Simulation, Clinical Pharmacology Sciences, Centocor Research and Development, Inc., Malvern, Pennsylvania 19355, USA. hzhou2@its.jnj.com
authors.forename: Honghui
authors.initials: H
authors.lastname: Zhou
authors.forename: Chuanpu
authors.initials: C
authors.lastname: Hu
authors.forename: Yaowei
authors.initials: Y
authors.lastname: Zhu
authors.forename: Ming
authors.initials: M
authors.lastname: Lu
authors.forename: Sam
authors.initials: S
authors.lastname: Liao
authors.forename: Newman
authors.initials: N
authors.lastname: Yeilding
authors.forename: Hugh M
authors.initials: HM
authors.lastname: Davis
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology*; D053759:Interleukin-23 / Q000276:immunology*; D007641:Keratolytic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D015990:Placebo Effect; D011565:Psoriasis / Q000188:drug therapy*; D012720:Severity of Illness Index; D016896:Treatment Outcome; D000069549:Ustekinumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053759:Interleukin-23; D007641:Keratolytic Agents; D018664:Interleukin-12; D000069549:Ustekinumab