k 8, the recommended subcutaneous maintenance dosing of 90 mg ustekinumab was administered every 8 weeks. Steady state ustekinumab concentration was achieved by the start of the second maintenance dose. There was no apparent accumulation in ustekinumab concentration over time when given subcutaneously every 8 weeks. Mean steady-state trough concentration was 2.51 ± 2.06 mcg/mL for 90 mg ustekinumab administered every 8 weeks.
Distribution
In a population pharmacokinetic analysis of ustekinumab, the volume of distribution of the central compartment was 2.74 L (95% CI: 2.69, 2.78), and the total volume of distribution at steady-state was 4.62 L in patients with Crohn's disease.
Elimination
The mean (±SD) half-life ranged from 14.9 ± 4.6 to 45.6 ± 80.2 days across all psoriasis studies following subcutaneous administration. In a population pharmacokinetic analysis of ustekinumab, the clearance was 0.19 L/day (95% CI: 0.185, 0.197) with an estimated median terminal half-life of approximately 19 days in patients with Crohn's disease.
Metabolism
The metabolic pathway of ustekinumab has not been characterized. As a human IgG1κ monoclonal antibody, ustekinumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
Specific Populations
Weight
When given the same dose, subjects with psoriasis or psoriatic arthritis weighing more than 100 kg had lower median serum ustekinumab concentrations compared with those subjects weighing 100 kg or less. The median trough serum concentrations of ustekinumab in subjects of higher weight (greater than 100 kg) in the 90 mg group were comparable to those in subjects of lower weight (100 kg or less) in the 45 mg group.
Age: Geriatric Population
A population pharmacokinetic analysis (N=106/1937 patients with psoriasis greater than or equal to 65 years old) was performed to eva luate the effect of age on the pharmacokinetics of ustekinumab. There were no apparent changes in pharmacokinetic parameters (clearance and volume of distribution) in subjects older than 65 years old.
Drug Interaction Studies
The effects of IL-12 or IL-23 on the regulation of CYP450 enzymes were eva luated in an in vitro study using human hepatocytes, which showed that IL-12 and/or IL-23 at levels of 10 ng/mL did not alter human CYP450 enzyme activities (CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4). However, the clinical relevance of in vitro data has not been established [see DRUG INTERACTIONS (7.3)].
No in vivo drug interaction studies have been conducted with STELARA®.
Population pharmacokinetic data analyses indicated that the clearance of ustekinumab was not impacted by concomitant MTX, NSAIDs, and oral corticosteroids, or prior exposure to a TNF blocker in patients with psoriatic arthritis.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal studies have not been conducted to eva luate the carcinogenic or mutagenic potential of STELARA®. Published literature showed that administration of murine IL-12 caused an anti-tumor effect in mice that contained transplanted tumors and IL-12/IL-23p40 knockout mice or mice treated with anti-IL-12/IL-23p40 antibody had decreased host defense to tumors. Mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone developed UV-induced skin cancers earlier and more frequently compared to wil |
