Adalimumab

Introduction to Adalimumab

Adalimumab (brand name Humira) is a fully human monoclonal antibody that targets tumor necrosis factor-alpha (TNF-α). It belongs to the class of biological disease-modifying antirheumatic drugs (bDMARDs) and is widely used in the treatment of various inflammatory conditions in both adults and children. Developed using phage display technology, adalimumab was first approved by the FDA in 2002 for rheumatoid arthritis and has since gained approval for numerous other indications.

In pediatrics, adalimumab has revolutionized the treatment of several chronic inflammatory conditions, offering improved quality of life and better disease control for many children who previously had limited therapeutic options.

Mechanism of Action

Adalimumab works by binding specifically to both soluble and transmembrane forms of TNF-α, a key pro-inflammatory cytokine involved in systemic inflammation. By neutralizing TNF-α, adalimumab:

  • Reduces inflammation by blocking TNF-α from binding to its receptors (TNFR1 and TNFR2) on cell surfaces
  • Modulates biological responses induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration
  • Induces apoptosis of TNF-producing cells, such as activated lymphocytes and monocytes
  • Downregulates the expression of other pro-inflammatory cytokines, chemokines, and tissue-degrading enzymes

This multi-faceted mechanism effectively suppresses the inflammatory cascade in various autoimmune and inflammatory disorders, leading to symptom relief and improved disease control.

Indications in Pediatrics

  • Juvenile Idiopathic Arthritis (JIA):
    • Approved for patients 2 years of age and older
    • Effective in polyarticular JIA, enthesitis-related arthritis, and psoriatic arthritis subtypes
    • Used as monotherapy or in combination with methotrexate
  • Crohn's Disease:
    • Approved for patients 6 years of age and older
    • Indicated for moderately to severely active Crohn's disease
    • Used in patients who have had inadequate response to conventional therapy or have lost response to infliximab
  • Ulcerative Colitis:
    • Approved for patients 5 years of age and older
    • Used for moderately to severely active ulcerative colitis
    • Effective in inducing and maintaining clinical remission
  • Plaque Psoriasis:
    • Approved for patients 4 years of age and older
    • Indicated for severe chronic plaque psoriasis
    • Used in patients who are candidates for systemic therapy or phototherapy
  • Hidradenitis Suppurativa:
    • Approved for patients 12 years of age and older
    • Used for moderate to severe hidradenitis suppurativa
  • Uveitis:
    • Approved for patients 2 years of age and older
    • Indicated for non-infectious intermediate, posterior, and panuveitis

Pharmacokinetics

  • Absorption:
    • Subcutaneous bioavailability: approximately 64%
    • Peak serum concentration (Cmax): 4.7 ± 1.6 μg/mL (40 mg dose)
    • Time to peak concentration (Tmax): 131 ± 56 hours
  • Distribution:
    • Volume of distribution (Vss): 4.7 to 6.0 L
    • Crosses the placenta but has minimal transfer into breast milk
  • Metabolism:
    • Not extensively metabolized
    • Eliminated primarily through proteolytic degradation
  • Elimination:
    • Half-life: approximately 2 weeks (range: 10-20 days)
    • Clearance: 12 mL/hour in adults (weight-dependent in children)
  • Pediatric considerations:
    • Clearance increases with body weight
    • Steady-state is typically achieved by 4 months in JIA patients

Dosage and Administration

Dosing varies based on the indication and patient's weight. All doses are administered subcutaneously.

  • Juvenile Idiopathic Arthritis:
    • 10 kg to <30 kg: 20 mg every other week
    • ≥30 kg: 40 mg every other week
  • Pediatric Crohn's Disease:
    • <40 kg:
      • Induction: 80 mg at week 0, 40 mg at week 2
      • Maintenance: 20 mg every other week starting at week 4
    • ≥40 kg:
      • Induction: 160 mg at week 0, 80 mg at week 2
      • Maintenance: 40 mg every other week starting at week 4
  • Pediatric Ulcerative Colitis:
    • 20 kg to <40 kg:
      • Induction: 80 mg at week 0, 40 mg at week 2
      • Maintenance: 40 mg every other week or 20 mg every week
    • ≥40 kg:
      • Induction: 160 mg at week 0, 80 mg at week 2
      • Maintenance: 80 mg every other week or 40 mg every week
  • Pediatric Plaque Psoriasis:
    • 13 kg to <30 kg: 20 mg every other week
    • ≥30 kg: 40 mg every other week
    • Start dose one week after initial dose

Administration technique:

  • Rotate injection sites to reduce the risk of injection site reactions
  • Allow the prefilled syringe or pen to reach room temperature before injection (15-30 minutes)
  • Do not shake the medication

Side Effects

Common side effects (≥1% of patients):

  • Injection site reactions (erythema, itching, pain, swelling)
  • Upper respiratory tract infections
  • Headache
  • Rash
  • Nausea, abdominal pain
  • Elevated liver enzymes
  • Back pain
  • Urinary tract infections
  • Hypertension

Serious side effects:

  • Increased risk of serious infections:
    • Tuberculosis (including reactivation of latent TB)
    • Invasive fungal infections (histoplasmosis, coccidioidomycosis)
    • Bacterial sepsis
    • Opportunistic infections
  • Malignancies:
    • Lymphoma (including hepatosplenic T-cell lymphoma)
    • Skin cancers (melanoma and non-melanoma)
  • Demyelinating disorders (multiple sclerosis, optic neuritis)
  • Lupus-like syndrome
  • Liver injury (including acute liver failure)
  • Cytopenias (pancytopenia, aplastic anemia)
  • Heart failure (new onset or worsening)
  • Hypersensitivity reactions (anaphylaxis, angioedema)

Monitoring

Before initiating therapy:

  • Screen for tuberculosis (TB):
    • Tuberculin skin test or interferon-gamma release assay
    • Chest X-ray
  • Test for hepatitis B virus (HBV):
    • HBsAg, anti-HBc, and anti-HBs
  • Baseline complete blood count (CBC)
  • Liver function tests (LFTs)
  • Assess for neurological symptoms or pre-existing demyelinating disorders

During therapy:

  • Monitor for signs and symptoms of infection
  • Periodic CBC (frequency based on individual risk factors)
  • Regular LFTs (e.g., every 3-6 months)
  • Annual TB screening in high-risk patients
  • Monitor for new or worsening neurological symptoms
  • Assess for autoantibody development (if symptoms suggestive of lupus-like syndrome)
  • Regular skin examinations for skin cancer
  • Monitor growth and development in pediatric patients

Treatment response monitoring:

  • Disease-specific activity scores (e.g., PCDAI for Crohn's disease, PASI for psoriasis)
  • Inflammatory markers (ESR, CRP)
  • Imaging studies as appropriate (e.g., MRI for JIA, endoscopy for IBD)

Drug Interactions

  • Live vaccines:
    • Avoid concurrent use due to increased risk of infection
    • Update vaccinations before initiating adalimumab when possible
  • Anakinra and abatacept:
    • Increased risk of serious infections
    • Concomitant use not recommended
  • Methotrexate:
    • May decrease adalimumab clearance
    • Often used in combination for enhanced efficacy in certain indications
  • CYP450 substrates:
    • Adalimumab may decrease CYP450 enzyme activity
    • Monitor drugs with narrow therapeutic indices (e.g., warfarin)
  • Other TNF-α inhibitors:
    • Concurrent use not recommended due to increased risk of adverse events

Special Populations

  • Pregnancy:
    • Category B
    • Crosses the placenta, especially in the third trimester
    • Consider risks and benefits; may be continued if clearly needed
  • Lactation:
    • Minimal transfer into breast milk
    • Generally considered compatible with breastfeeding
  • Renal impairment:
    • No dose adjustment necessary
  • Hepatic impairment:
    • No specific dose adjustment recommendations
    • Use with caution; monitor liver function closely
  • Elderly:
    • No specific dose adjustment
    • Higher risk of infections and malignancies; monitor closely


Further Reading
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