Population exposure-response model to support dosing evaluation of ixekizumab in
patients with chronic plaque psoriasis.
Author(s): Tham LS(1), Tang CC, Choi SL, Satterwhite JH, Cameron GS, Banerjee S.
Affiliation(s): Author information:
(1)Lilly-NUS Centre for Clinical Pharmacology, Singapore.
Publication date & source: 2014, J Clin Pharmacol. , 54(10):1117-24
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.
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