title: Population exposure-response model to support dosing evaluation of ixekizumab in patients with chronic plaque psoriasis.
abstract: Ixekizumab (LY2439821), a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody that selectively binds and neutralizes interleukin (IL) 17A has demonstrated efficacy in the treatment of psoriasis. A population pharmacokinetics-pharmacodynamics model was developed using NONMEM 7.2 to describe the temporal relationship between ixekizumab concentrations and absolute Psoriasis Area and Severity Index (PASI) scores from a phase 2 dose-finding study in chronic plaque psoriasis. The objective was to inform dose-selection for further development. The primary endpoint, PASI 75 (75% or greater improvement from baseline PASI score) was then derived from each individual's absolute PASI score. The population pharmacokinetics of ixekizumab was characterized by a two-compartment model, while the exposure-response relationship was characterized using an indirect response model that described the pharmacological effects of ixekizumab and placebo in the form of inhibition of the formation of psoriatic skin lesions. PASI 75 responder status at the Week 12 primary endpoint was found to be a significant covariate on the concentration producing half maximal effect (EC50 ). While the results suggested patient may have different levels of sensitivity to ixekizumab, it is possible that nonresponder patients assigned to lower doses of ixekizumab may potentially become responders to ixekizumab if given doses that yield adequate exposures.
authors.affiliation: Lilly-NUS Centre for Clinical Pharmacology, Singapore.
authors.forename: Lai-San
authors.initials: LS
authors.lastname: Tham
authors.forename: Cheng-Cai
authors.initials: CC
authors.lastname: Tang
authors.forename: Siak-Leng
authors.initials: SL
authors.lastname: Choi
authors.forename: Julie H
authors.initials: JH
authors.lastname: Satterwhite
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Cameron
authors.forename: Subhashis
authors.initials: S
authors.lastname: Banerjee
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008954:Models, Biological; D017711:Nonlinear Dynamics; D011565:Psoriasis / Q000188:drug therapy* / Q000473:pathology; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C549079:ixekizumab
keywords: exposure-response; pharmacometrics; population pharmacokinetics pharmacodynamics; psoriasis