"Oct. 17, 2012 -- A drug used to treat psoriasis may provide a much-needed option for people with bad cases of Crohn's disease.
In the new study, some people with moderate to severe Crohn's given Stelara (ustekinumab) began to see imp"...
Mechanism of Action
Ustekinumab is a human IgG1κ monoclonal antibody that binds with high affinity and specificity to the p40 protein subunit used by both the interleukin (IL)-12 and IL-23 cytokines. IL-12 and IL-23 are naturally occurring cytokines that are involved in inflammatory and immune responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation. In in vitro models, ustekinumab was shown to disrupt IL-12 and IL-23 mediated signaling and cytokine cascades by disrupting the interaction of these cytokines with a shared cell-surface receptor chain, IL-12 β1.
In a small exploratory study, a decrease was observed in the expression of mRNA of its molecular targets IL-12 and IL-23 in lesional skin biopsies measured at baseline and up to two weeks posttreatment in psoriatic subjects.
In psoriasis subjects, the median time to reach the maximum serum concentration (Tmax) was 13.5 days and 7 days, respectively, after a single subcutaneous administration of 45 mg (N=22) and 90 mg (N=24) of ustekinumab. In healthy subjects (N=30), the median Tmax value (8.5 days) following a single subcutaneous administration of 90 mg of ustekinumab was comparable to that observed in psoriasis subjects. Following multiple subcutaneous doses of STELARA®, the steady-state serum concentrations of ustekinumab were achieved by Week 28. The mean (±SD) steady-state trough serum concentration ranged from 0.31 ± 0.33 mcg/mL (45 mg) to 0.64 ± 0.64 mcg/mL (90 mg). There was no apparent accumulation in serum ustekinumab concentration over time when given subcutaneously every 12 weeks.
Following subcutaneous administration of 45 mg (N=18) and 90 mg (N=21) of ustekinumab to psoriasis subjects, the mean (±SD) apparent volume of distribution during the terminal phase (Vz/F) was 161 ± 65 mL/kg and 179 ± 85 mL/kg, respectively. The mean (± SD) volume of distribution during the terminal phase (Vz) following a single intravenous administration to subjects with psoriasis ranged from 56.1 ± 6.5 to 82.1 ± 23.6 mL/kg.
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.
The mean (± SD) systemic clearance (CL) following a single intravenous administration of ustekinumab to psoriasis subjects ranged from 1.90 ± 0.28 to 2.22 ± 0.63 mL/day/kg. The mean (±SD) half-life ranged from 14.9 ± 4.6 to 45.6 ± 80.2 days across all psoriasis studies following intravenous and subcutaneous administration.
When given the same dose, subjects weighing > 100 kg had lower median serum ustekinumab concentrations compared with those subjects weighing ≤ 100 kg. The median trough serum concentrations of ustekinumab in subjects of higher weight ( > 100 kg) in the 90 mg group were comparable to those in subjects of lower weight ( ≤ 100 kg) in the 45 mg group.
Hepatic and Renal Impairment
No pharmacokinetic data are available in patients with hepatic or renal impairment.
A population pharmacokinetic analysis (N=106/1937 subjects greater than or equal to 65 years old) was performed to evaluate 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.
The effects of IL-12 or IL-23 on the regulation of CYP450 enzymes were evaluated 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].
Animal Toxicology and/or Pharmacology
In a 26-week toxicology study, one out of 10 monkeys subcutaneously administered 45 mg/kg ustekinumab twice weekly for 26 weeks had a bacterial infection.
Two multicenter, randomized, double-blind, placebo-controlled studies (STUDY 1 and STUDY 2) enrolled a total of 1996 subjects 18 years of age and older with plaque psoriasis who had a minimum body surface area involvement of 10%, and Psoriasis Area and Severity Index (PASI) score > 12, and who were candidates for phototherapy or systemic therapy. Subjects with guttate, erythrodermic, or pustular psoriasis were excluded from the studies.
STUDY 1 enrolled 766 subjects and STUDY 2 enrolled 1230 subjects. The studies had the same design through Week 28. In both studies, subjects were randomized in equal proportion to placebo, 45 mg or 90 mg of STELARA®. Subjects randomized to STELARA® received 45 mg or 90 mg doses, regardless of weight, at Weeks 0, 4, and 16. Subjects randomized to receive placebo at Weeks 0 and 4 crossed over to receive STELARA® (either 45 mg or 90 mg) at Weeks 12 and 16.
In both studies, the endpoints were the proportion of subjects who achieved at least a 75% reduction in PASI score (PASI 75) from baseline to Week 12 and treatment success (cleared or minimal) on the Physician's Global Assessment (PGA). The PGA is a 6-category scale ranging from 0 (cleared) to 5 (severe) that indicates the physician's overall assessment of psoriasis focusing on plaque thickness/induration, erythema, and scaling.
In both studies, subjects in all treatment groups had a median baseline PASI score ranging from approximately 17 to 18. Baseline PGA score was marked or severe in 44% of subjects in STUDY 1 and 40% of subjects in STUDY 2. Approximately two-thirds of all subjects had received prior phototherapy, 69% had received either prior conventional systemic or biologic therapy for the treatment of psoriasis, with 56% receiving prior conventional systemic therapy and 43% receiving prior biologic therapy. A total of 28% of study subjects had a history of psoriatic arthritis.
The results of STUDY 1 and STUDY 2 are presented in Table 3 below.
Table 3: Clinical Outcomes STUDY 1 and STUDY 2
|Week 12||Placebo||STUDY 1||Placebo||STUDY 2|
|45 mg||90 mg||45 mg||90 mg|
|PASI 75 response||8 (3%)||171 (67%)||170 (66%)||15 (4%)||273 (67%)||311 (76%)|
|PGA of Cleared or Minimal||10 (4%)||151 (59%)||156 (61%)||18 (4%)||277 (68%)||300 (73%)|
Examination of age, gender, and race subgroups did not identify differences in response to STELARA® among these subgroups.
In subjects who weighed < 100 kg, response rates were similar with both the 45 mg and 90 mg doses; however, in subjects who weighed > 100 kg, higher response rates were seen with 90 mg dosing compared with 45 mg dosing (Table 4 below).
Table 4: Clinical Outcomes
by Weight STUDY 1 and STUDY 2
|Placebo||STUDY 1||Placebo||STUDY 2|
|45 ms||90 me||45 mg||90 mg|
|PASI 75 response at Week 12*|
|≤ 100 kg||4%||74%||65%||4%||73%||78%|
|> 100 kg||2%||54%||68%||3%||49%||71%|
|PGA of Cleared or Minimal at Week 12*|
|≤ 100 kg||4%||64%||63%||5%||74%||75%|
|> 100 kg||3%||49%||58%||3%||51%||69%|
|*Patients were dosed with study medication at Weeks 0 and 4.|
Subjects in STUDY 1 who were PASI 75 responders at both Weeks 28 and 40 were re-randomized at Week 40 to either continued dosing of STELARA® (STELARA® at Week 40) or to withdrawal of therapy (placebo at Week 40). At Week 52, 89% (144/162) of subjects re-randomized to STELARA® treatment were PASI 75 responders compared with 63% (100/159) of subjects re-randomized to placebo (treatment withdrawal after Week 28 dose). The median time to loss of PASI 75 response among the subjects randomized to treatment withdrawal was 16 weeks.
Last reviewed on RxList: 5/17/2013
This monograph has been modified to include the generic and brand name in many instances.
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