Biological Therapies Anti-IL-12/23 (Ustekinumab) and Anti-IL-23 (Guselkumab, Risankizumab)

Mechanism

Pharmacological Class and Group

Selective immunobiologicals. Ustekinumab is an IgG1κ monoclonal antibody directed against the common p40 subunit of the cytokines IL-12 and IL-23. Guselkumab (IgG1λ) and Risankizumab (IgG1) are monoclonal antibodies selectively and specifically directed against the p19 subunit of IL-23.

Mechanism of Action

IL-23 is a key upstream cytokine in the psoriasis pathogenic cascade, directly responsible for the differentiation, survival and clonal expansion of pathogenic Th17 lymphocytes in the cutaneous dermis.

Selective Axis Locking Mechanism p40 and p19

1. Ustekinumab (Dual IL-12/IL-23 Blockade): Selectively binds to the 40 kDa peptide protein subunit (p40) shared by the cytokines IL-12 and IL-23, preventing their binding to the homologous cellular receptors IL-12Rβ1 expressed on naïve T cells (synergistically blocking Th1 and IL-23 differentiation pathways). Th17).

2. Guselkumab and Risankizumab (Selective IL-23 Blockade): They specifically bind to the unique 19 kDa subunit (p19) of the cytokine IL-23, terminally blocking its interaction with its coupled receptor IL-23R:

Anti-p19 (Risankizumab) + IL-23 (p19) Blockade of IL-23R Inhibition of Th17 Expansion and ↓ IL-17A/F

By selectively blocking IL-23 without altering the IL-12 pathway (mediator of antiviral and antitumor defense of the Th1 pathway), p19 inhibitors (Guselkumab, Risankizumab) offer an excellent biosafety profile with very sustained long-term clinical remissions.

Pharmacokinetics

High Resolution Pharmacokinetics

• Absorption and Routes: Subcutaneous (SC) administration. Ustekinumab has a bioavailability of 57%, with a plasma peak at 7-14 days. Risankizumab has a slow and progressive absorption with bioavailability of 60%, reaching serum peaks 3-14 days post-injection.
• Distribution: Low tissue distribution volume, predominantly confined to the dermoepidermal and local lymphatic compartment.
• Half-life (t_1/2): Ustekinumab has a prolonged terminal elimination half-life of 15 to 45 days, allowing dosing regimens spaced every 12 weeks. Guselkumab has a half-life of 15-18 days. Risankizumab has an exceptionally long half-life of 20 to 28 days, facilitating convenient dosing schedules every 12 weeks (4 doses per year).

Indicators and dose

Clinical Indications and Off-Label Uses

• Moderate to Severe Plaque Psoriasis: First-line and highly effective drugs in adults and pediatrics (Ustekinumab).
• Active Psoriatic Arthritis: Highly effective treatment for joint inflammation and dactylitis.
• Inflammatory Bowel Disease (Crohn's Disease and Ulcerative Colitis): Ustekinumab and Risankizumab are approved for the control of moderate-severe intestinal mucosal inflammation.

Dosage and Clinical Adjustment

Ustekinumab (Plaque Psoriasis):

• Dosage based on Body Weight (Adults):
  • Weight 100 kg: 45 mg administered subcutaneously in week 0 and week 4, followed by maintenance doses of 45 mg every 12 weeks continuously.
  • Weight > 100 \, \text{kg}$: 90 mg administered subcutaneously at week 0 and week 4, followed by maintenance doses of 90 mg every 12 weeks continuously.

Guselkumab (Tremfya):

• Dosage Schedule: 100 mg subcutaneously administered in week 0 and week 4, followed by maintenance doses of 100 mg every 8 weeks continuously.

Risankizumab (Skyrizi):

• Dosage Schedule: 150 mg subcutaneously (given as a 150 mg injection via prefilled syringe) at week 0 and week 4, followed by maintenance doses of 150 mg every 12 weeks continuously.

Adjustment in Renal / Hepatic Failure: No dose adjustment is required in patients with renal or hepatic failure, since the clearance of immunoglobulins is carried out through non-specific proteolytic catabolic routes.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Hypersensitivity to the active ingredient or to proteins derived from the formulation.
• Clinically serious active bacterial, fungal, or viral infections (e.g., sepsis or active tuberculosis).

Relative Contraindications

• Pregnancy in progress (restrict as a general precaution).
• Latent Tuberculosis Infection not treated prophylactically.

Adverse Effects (ADR) and Specific Toxicity

• Very common (>10%): Mild self-limited headache, benign nasopharyngitis.
• Common (1%-10%): Transient erythema or pain reactions at the subcutaneous injection site, fatigue, self-limited diarrhea, fungal skin infections (ringworm, mild superficial candidiasis).
• Uncommon (0.1%-1%): Superficial dermal-epidermal bacterial cellulitis at the injection site, immediate hypersensitivity reactions (urticaria), reactivation of latent tuberculosis (extremely low reactivation rate compared historically with anti-TNF agents).

Class Differentiation: The Dosage Convenience of Anti-IL-23

Selective IL-23 inhibitors, particularly Risankizumab, represent a milestone in dosage adherence and long-term control in psoriasis. After the induction phase of two initial doses separated by 4 weeks, the stable maintenance regimen is carried out by a single subcutaneous injection every 12 weeks (just 4 doses per year), managing to maintain a persistent PASI 90/100 skin clearance in more than 80% of patients treated continuously.

Drug Interactions of Clinical Relevance

• Live Attenuated Vaccines: Absolute contraindication due to risk of development of uncontrolled disseminated infection.
• They do not interfere with hepatic clearance mediated by enzymes of the CYP450 system.

Safety in Pregnancy and Breastfeeding

• Pregnancy: Not recommended. They cross the placental barrier actively in the second and third gestational trimesters. Preclinical reproductive toxicity studies in primates with supraphysiological doses did not show fetal harm, but it is preferred to discontinue treatment out of clinical precautionary principle.
• Breastfeeding: Compatible. It is excreted in minute quantities of no significance in human milk and is disintegrated in the stomach of the newborn.