Integrated Population Pharmacokinetic Analysis of Ustekinumab Across Multiple Immune-Mediated Inflammatory Disease Populations and Healthy Subjects

Background and Objectives Ustekinumab has been approved for the treatment of patients with plaque psoriasis (PSO), psoriatic arthritis (PSA), Crohn's disease (CD), and ulcerative colitis (UC). This study was performed to investigate whether the pharmacokinetics of ustekinumab differ across different disease populations. Methods An integrated population pharmacokinetic analysis was conducted to characterize ustekinumab pharmacokinetics across four disease indications (i.e., PSO, PSA, CD, and UC) and healthy subjects. Results The pooled ustekinumab pharmacokinetic data consisted of 46,970 serum concentrations from 3,217 subjects (n = 356 for PSO, 696 for PSA, 1196 for CD, 823 for UC, and 24 for healthy subjects) in 7 clinical trials following subcutaneous or intravenous ustekinumab administrations. The pharmacokinetics of ustekinumab were adequately described by a two-compartment linear model with first-order absorption and elimination. Ustekinumab clearance (CL) and volume of distribution parameters increased nonlinearly with body weight, and the CL was higher in subjects with lower serum albumin, non-Caucasians, and positive antibodies to ustekinumab. Although CL in subjects with PSO and PSA appeared to be slightly different (- 12.7% and + 8.87%, respectively) from CL in other populations (including CD, UC, and healthy subjects), the model-derived post-hoc pharmacokinetic parameters were generally comparable across the 4 disease populations. Simulations also suggested overall comparable ustekinumab exposure (i.e., trough concentration and AUC) at steady state across the disease populations following the same subcutaneous dose regimen. Conclusions Ustekinumab pharmacokinetics are generally comparable across all approved inflammatory-mediated indications and healthy subjects after accounting for the body weight-related pharmacokinetic difference.