Clinical Information

Drug and target:

Ustekinumab (UTK) is a fully human IgG1 kappa monoclonal antibody (1) that binds with high affinity to the p40 subunit of human interleukin (IL)-12 and IL-23. The drug prevents IL-12 and IL-23 bioactivity by binding and neutralizing the shared p40 subunit, preventing interaction with the cell surface receptor protein IL-12Rbeta1. Through this mechanism of action, UTK effectively neutralizes IL-12 and IL-23, proteins that are thought to be associated with gastrointestinal inflammation in Crohn disease (CD) and ulcerative colitis (UC). The reference product for ustekinumab is Stelara (Johnson & Johnson). Several biosimilars are US Food and Drug Administration (FDA)-approved for ustekinumab as of December 2025: ustekinumab-auub (Wezlana, Amgen or Yesintek, Samsung Bioepis/Organon), ustekinumab-aauz (Otulfi, Fresenius Kabi), and ustekinumab-stba (Steqeyma, Sandoz).

Indications:

Ustekinumab is FDA-approved for the treatment of patients with moderate to severe CD, moderate to severe UC, psoriatic arthritis, and plaque psoriasis. The drug is FDA-approved for pediatric patients 6 years and older for moderate to severe plaque psoriasis and active psoriatic arthritis. Approval for pediatric CD and UC is still pending as of December 2025. Doses vary by indication. In the setting of the inflammatory bowel diseases (IBD), CD and UC, the treatment regimen is started with a single weight-based loading dose of the t-mab administered intravenously (IV), and a maintenance regimen with 90 mg standard (non-weight based) subcutaneous administration of ustekinumab 8 weeks after induction dose, and every 8 weeks thereafter.

Pharmacokinetic highlights:

Ustekinumab half-life ranges from 15 to 32 days, with a median of approximately 3 weeks, consistent with other IgG1 monoclonal antibodies. Steady state is achieved after 16 to 20 weeks of treatment. Before then, the serum concentrations of UTK may vary significantly.

Immunogenicity:

In clinical trials, 6% to 12.4% of patients using ustekinumab for psoriasis or psoriatic arthritis developed low-titer antibodies to ustekinumab (ATU).(1) For IBD, between 2.9% and 4.6% of patients developed ATU when treated with ustekinumab for 1 year.(1) In clinical practice, persistent ATU are observed in less than 2% of tested patients. Ustekinumab is associated with lower immunogenicity than anti-tissue necrosis factor inhibitors.(2) ATU may increase drug clearance in treated patients or neutralize the drug effect, thereby potentially contributing to the loss of response. ATU could also cause adverse events, such as serum sickness and hypersensitivity reactions.

Evidence for therapeutic drug monitoring:

Higher ustekinumab concentrations post-induction and during maintenance correlate with better outcomes in IBD.(2-4) At the end of induction (week 8), a threshold trough greater than 3.5 mcg/mL has been associated with clinical response. During maintenance (every-8-weeks dosing), trough concentrations targets between 3 to 7 mcg/mL are associated with clinical response and remission. These data come from post hoc analyses and cohort studies.(3-5) Ustekinumab clearance can be faster in heavier patients. There is little data supporting proactive TDM for ustekinumab, with recent reports suggesting decreased IBD-related hospitalization (6) and less disease activity (7) with higher ustekinumab concentrations. Reactive monitoring is employed when response is suboptimal.(2,3) Subtherapeutic trough concentrations are most often due to increased drug clearance related to inflammatory burden or body weight and are commonly managed by dose interval shortening rather than addition of immunomodulator therapy.

Ustekinumab quantitation is performed in conjunction with immunogenicity assessment for ATU.