Ustekinumab
Ustekinumab Uses, Dosage, Side Effects, Food Interaction and all others data.
Ustekinumab is a human immunoglobulin (Ig) G1 kappa monoclonal antibody directed against interleukin(IL)-12 and IL-23, which are cytokines that are involved in immune and inflammatory responses. It was generated via recombinant human IL-12 immunization of human Ig (hu-Ig) transgenic mice. It is a targeted biologic disease-modifying anti-rheumatic drug (bDMARDs) that is used in the management of various inflammatory conditions that involve the activation of IL-12 and IL-23 signalling pathways.
The therapeutic use of the drug started in Canada, the US, and Europe since 2009 when it was first approved for the treatment of adult patients with moderate to severe plaque psoriasis and active psoriatic arthritis, alone or in combination with methotrexate. In September 2016, ustekinumab was additionally approved for the management of moderate to severe Crohn's disease in selected adult patients. In October 2019, it was also approved by the FDA for use to manage moderately to severely active ulcerative colitis in adults. Ustekinumab is currently the first and only approved biologic therapy for ulcerative colitis that targets the interleukin (IL)-12 and IL-23 cytokines. The dosing regimen for ustekinumab is based on the patient's weight and there are intravenous and subcutaneous formulations of the drug based on the dosing schedule and condition being treated. Ustekinumab is commonly marketed under the trade name STELARA.
Ustekinumab is a targeted antibody therapy that suppresses immune responses. It acts by reducing the signaling pathways of pro-inflammatory cytokines IL-12 and IL-23, which play a role in various inflammatory conditions. It downregulates the gene expression of inflammatory cytokines and chemokines such as MCP-1, TNF-alpha, IP-10, and IL-8. The formation of cytochrome P-450 enzymes may be altered by elevated levels of certain cytokines during chronic inflammation. Research shows that there is an inverse relationship between plasma levels of inflammatory cytokines and CYP450 enzyme formation and activity. While ustekinumab may potentially normalize the formation of CYP enzymes and enhance the CYP-mediated metabolism of drugs, there were no clinically significant effects on human CYP enzyme activities. The steady-state was achieved by 28 weeks after multiple subcutaneous dose administration in adult patients with psoriasis.
| Trade Name | Ustekinumab |
| Availability | Prescription only |
| Generic | Ustekinumab |
| Ustekinumab Other Names | Stelera, Ustekinumab |
| Related Drugs | Stelara, Entyvio, Humira, Otezla, Cosentyx, Zeposia, Colazal, prednisone, methotrexate, dexamethasone |
| Weight | 5mg/ml, 45mg/0.5ml, 90mg/ml, |
| Type | Intravenous Solution, Subcutaneous Solution, Subcutaneous |
| Weight | 148600.0 Da (approximate) |
| Protein binding | There is no information on plasma protein binding of ustekinumab. |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Ustekinumab is a targeted antibody therapy used to manage inflammatory conditions such as plaque psoriasis, psoriatic arthritis, Crohn's Disease, and ulcerative colitis.
Ustekinumab is indicated for the management of moderate to severe plaque psoriasis in children aged 6 and above, adolescents, and adults who are candidates for phototherapy or systemic therapy.
It is indicated for the management of active psoriatic arthritis in adults, alone or in combination with methotrexate.
It is indicated for the management of moderately to severely active Crohn’s disease in adults who were clinically unresponsive or intolerant to immunomodulator or corticosteroid therapy (but never failed a tutor necrosis factor (TNF) blocker) or treatment with one or more TNF blockers.
It is indicated for the management of moderately to severely active ulcerative colitis in adults.
Ustekinumab is also used to associated treatment for these conditions: Psoriatic arthritis aggravated, Severe Plaque psoriasis, Ulcerative Colitis, Active Severe, Moderate Plaque psoriasis, Moderate Ulcerative colitis, Moderate, active Crohn´s Disease, Severe, active Crohn´s Disease
How Ustekinumab works
Interleukin (IL)-12 and IL-23 are heterodimeric cytokines that evoke immune and inflammatory responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation. The role of IL-12 and IL-23 were implicated in a variety of chronic inflammatory conditions, such as psoriasis and inflammatory bowel diseases. They modulate lymphocyte function, including T-helper (Th) 1 and Th17 cell subsets, as CD4+ T cells can differentiate into T-helper (Th) effector lineages based on the environment. Th cells can further activate the downstream pro-inflammatory mediators and transcription factors such as TNFα and IFNγ that drive innate and adaptive immunity.
IL-12 and IL-23 share a common p40 subunit, paired with p35 and p19 subunits of IL-12 and IL-23, respectively. The antigen-binding fragment (Fab) of ustekinumab binds the D1 domain of the p40 subunit of IL-12 and IL-23 in a 1:1 ratio. This prevents IL-12 and IL-23 from binding to the IL-12Rβ1 receptor chain of IL-12 (IL-12Rβ1/β2) and IL-23 (IL-12Rβ1/23R) receptor complexes on the surface of NK and T cells. Ustekinumab only binds to IL-12 and IL-23 that are unbound to IL-12Rβ1, so it is unlikely to initiate Fc effector functions, such as ADCC or CDC. Inhibition of the IL-12/23 signalling pathway leads to profound suppression of both the Th1 and Th17 cell lineage of cytokines and chemokines and their inflammatory pathways.
Toxicity
Signs of dose-limiting toxicity were not observed with intravenous administration of single doses up to 6 mg/kg in clinical trials. Information on overdose of ustekinumab is limited: in the event of overdose, patients should be monitored for any signs and symptoms of drug-related adverse events and appropriate symptomatic treatment should be initiated.
Food Interaction
No interactions found.Ustekinumab Hypertension interaction
[Major] The use of ustekinumab may cause posterior leukoencephalopathy syndrome.
One case of reversible posterior leukoencephalopathy syndrome (RPLS) was observed in clinical studies of psoriasis and psoriatic arthritis.
No cases of RPLS were observed in clinical studies of Crohn's disease.
Conditions with which it has been associated include preeclampsia, eclampsia, acute hypertension, cytotoxic agents and immunosuppressive therapy.
Caution and close monitoring is advised when prescribing this agent to patients at risk of RPLS.
It is recommended to administer appropriate treatment and discontinue therapy if RPLS is suspected.
Ustekinumab Drug Interaction
Major: infliximabModerate: lactobacillus acidophilus, methylprednisoloneUnknown: 5-hydroxytryptophan, rabeprazole, charcoal, contained in alcoholic beverages , clomiphene, sulfamethoxazole / trimethoprim, ubiquinone, copper gluconate, magnesium sulfate, glycerin, metoprolol, acetaminophen, mesalamine, bioflavonoids, acetaminophen, iron sucrose, cholecalciferol
Ustekinumab Disease Interaction
Major: malignancies, posterior leukoencephalopathy syndromeModerate: infections, tuberculosis, immunizations
Volume of Distribution
The total volume of distribution at steady-state was 4.62 L in patients with Crohn’s disease and 4.4 L in patients with ulcerative colitis. The median apparent volume of distribution during the terminal phase (Vz/F) ranged from 76 to 161 mL/kg in patients with psoriasis receiving a single subcutaneous dose.
Elimination Route
The median Tmax following a single subcutaneous dose administration of 45mg and 90mg in adults with psoriasis was 13.5 days and 7 days, respectively. The median Cmax in the same group of patients was 2.4 μg/mL and 5.3 μg/mL at doses of 45mg and 90mg, respectively. The median AUC was 84.9 μg·day/mL and 226.9 μg·day/mL, respectively. Following an intravenous induction dose administration, the mean ± SD Cmax was 125.2 ± 33.6 mcg/mL in patients with Crohn’s disease and 129.1 ± 27.6 mcg/mL in patients with ulcerative colitis.
The systemic exposure of ustekinumab (Cmax and AUC) increases in a linear or dose-proportional manner following a single subcutaneous administration at doses ranging from approximately 24 mg to 240 mg in patients with psoriasis. The estimated absolute bioavailability (F) of ustekinumab following a single subcutaneous dose administration in patients with psoriasis is 57.2%.
Half Life
Following administration of a single subcutaneous dose of 45 mg or 90 mg in patients with psoriasis, the median half-life was 19.8 days and 21.2, respectively. The estimated median terminal half-life of approximately 19 days in patients with Crohn’s disease or ulcerative colitis.
Clearance
The median apparent clearance (CL/F) following a single subcutaneous administration to patients with psoriasis ranged from 2.7 to 5.3 mL/day/kg. In patients with Crohn’s disease, the clearance was 0.19 L/day in patients with Crohn’s disease or ulcerative colitis.
Elimination Route
There is limited information on the main route of elimination of ustekinumab; it is expected to undergo renal excretion following degradation.
Innovators Monograph
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