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Monday, August 11, 2025

Hereditary angioedema agents


Overview

  • Hereditary angioedema (HAE) is a rare genetic disorder caused by deficiency or dysfunction of C1 esterase inhibitor (C1-INH) or dysregulation of bradykinin production

  • Characterized by recurrent episodes of non-pitting swelling of the skin, gastrointestinal tract, and airway

  • Not mediated by histamine – antihistamines, corticosteroids, and epinephrine are generally ineffective

  • HAE agents target different points in the bradykinin pathway to either prevent attacks (prophylaxis) or treat acute episodes

Mechanism of Disease in HAE

  • C1-INH deficiency or dysfunction → uncontrolled activation of kallikrein → excessive bradykinin

  • Bradykinin increases vascular permeability → tissue swelling

Drug Classes Used in HAE

1. C1 Esterase Inhibitor (C1-INH) Replacement Therapies

  • Mechanism: Replace deficient/dysfunctional C1-INH, restoring regulation of complement, contact, and fibrinolytic systems

  • Formulations:

    • Plasma-derived C1-INH: Berinert (acute), Cinryze (prophylaxis)

    • Recombinant C1-INH: Ruconest (acute)

  • Routes: Intravenous for acute or prophylactic use, subcutaneous for prophylaxis (Haegarda)

2. Plasma Kallikrein Inhibitors

  • Mechanism: Direct inhibition of plasma kallikrein, reducing bradykinin production

  • Agents:

    • Lanadelumab (Takhzyro) – subcutaneous prophylaxis

    • Berotralstat (Orladeyo) – oral prophylaxis

    • Ecallantide (Kalbitor) – subcutaneous acute treatment

3. Bradykinin B2 Receptor Antagonists

  • Mechanism: Block bradykinin from binding to B2 receptors, preventing increased vascular permeability

  • Agent: Icatibant (Firazyr) – subcutaneous acute treatment

Acute Attack Management

  • Berinert (IV C1-INH) – approved for acute attacks in adults and children

  • Ruconest (IV recombinant C1-INH) – acute treatment in adults and adolescents

  • Icatibant – rapid subcutaneous self-administration possible

  • Ecallantide – subcutaneous, requires administration by a healthcare professional due to risk of anaphylaxis

Long-Term Prophylaxis

  • Cinryze (IV C1-INH) – approved for prophylaxis in adults, adolescents, and children

  • Haegarda (subcutaneous C1-INH) – for routine prevention in adults and adolescents

  • Lanadelumab – every 2–4 weeks subcutaneous injection, long half-life

  • Berotralstat – once daily oral prophylaxis, convenient for non-injectable option

Adverse Effects

  • C1-INH products: Injection site reactions, headache, possible thromboembolic risk (rare)

  • Lanadelumab: Injection site pain, hypersensitivity

  • Berotralstat: GI symptoms (abdominal pain, diarrhea), liver enzyme elevations

  • Icatibant: Injection site reactions in most patients, transient

  • Ecallantide: Risk of anaphylaxis (black box warning), headache, fever

Contraindications and Precautions

  • Known hypersensitivity to product components

  • Ecallantide: avoid in patients with a history of hypersensitivity reactions

  • Monitor for thromboembolic risk with repeated high-dose C1-INH

  • Dose adjustments may be needed in hepatic or renal impairment (especially with berotralstat)

Drug Interactions

  • ACE inhibitors: Contraindicated in HAE patients as they increase bradykinin levels and may worsen attacks

  • No major CYP-mediated interactions for most HAE biologics, but berotralstat is metabolized by CYP2D6 and CYP3A4 (possible interactions with strong inhibitors/inducers)




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