Dosage Optimization of Nemolizumab Using Population Pharmacokinetic and Pharmacokinetic-Pharmacodynamic Modeling and Simulation.

Nemolizumab is a humanized anti-interleukin-31 receptor A monoclonal antibody for treating atopic dermatitis, and it especially improves pruritus. The objective of the simulation study was to optimize the dose regimen using a flat dose. The serum nemolizumab concentration and pruritus visual analog scale as an efficacy end point were modeled using the population analysis approach in 299 patients with atopic dermatitis who received placebo or doses between 0.1 and 3 mg/kg as a single dose once every 4 weeks or 2 mg/kg once every 8 weeks. A 1-compartment model with first-order absorption was employed as the pharmacokinetic model. An indirect turnover model with an inhibition component was employed as the main part of the pharmacokinetic-pharmacodynamic model. The models well described the observations. Therefore, simulations with several dose regimens were performed to optimize the dose regimen including a flat dose. The simulated area under the concentration-time curve at a steady state around 75 mg in the every-4-week regimen corresponds to that associated with the dose range of 0.5 to 2 mg/kg in the 4-week regimen. The simulated pruritus visual analog scale also showed a similar tendency. These simulation results support dose optimization during the clinical development program of nemolizumab.