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.

BackgroundThe efficacy of ixekizumab, an anti‐interleukin‐17A (anti‐IL‐17A) monoclonal IgG4 antibody, was demonstrated in moderate‐to‐severe psoriasis patients when administered via prefilled syringe (PFS).ObjectiveTo evaluate the effect of two drug delivery devices on the pharmacokinetics (PK) of ixekizumab as well as efficacy and safety with both devices.MethodsIn the first 12 weeks of an open‐label, phase 3 study, moderate‐to‐severe psoriasis patients were randomized to ixekizumab delivery via PFS or autoinjector device. Randomization was stratified by weight (<80 kg, 80–100 kg, >100 kg), injection assistance (yes/no) and injection site (arm, thigh or abdomen). Following a 160‐mg initial dose at week 0, patients received subcutaneous 80‐mg ixekizumab as a single injection every 2 weeks for 12 weeks. Blood samples were collected following the initial 160‐mg dose on days 2, 4, 7, 10 and 14 for PK analysis. Primary PK parameters were maximum concentration (C max) and area under the curve (AUC 0‐tlast) where t last is the time of last sample (14 days ± 24 h). Efficacy was assessed by percent improvement on the Psoriasis Area and Severity Index (PASI) at week 12. Adverse event reporting, vital signs and clinical laboratory data were used to evaluate safety.ResultsOf 204 randomized patients, 192 were included in the PK analysis (PFS: 94; autoinjector: 98). The PFS and autoinjector showed similar geometric mean C max (90% CI) [15.0 μg/mL (13.9–16.1) vs. 14.8 μg/mL (13.8–15.9)] and geometric mean AUC 0‐tlast (90% CI) [157 μg × day/mL (147–168) vs. 154 μg × day/mL (144–165)]. When comparing C max and AUC 0‐tlast of the autoinjector to PFS, the geometric LS mean ratios were 0.97. At week 12, mean percent PASI improvement (via modified baseline observation carried forward) was similar with the PFS (89.3%) and autoinjector (86.9%). Both devices had safety results that were consistent with the known safety profile of ixekizumab.ConclusionThe PK, efficacy and safety of ixekizumab administered subcutaneously by PFS and autoinjector were similar. Clinicaltrials.gov number: NCT01777191 https://clinicaltrials.gov/ct2/show/NCT01777191