Ravulizumab

Introduction to Ravulizumab

Ravulizumab (brand name Ultomiris) is a long-acting C5 complement inhibitor developed by Alexion Pharmaceuticals. It is a humanized monoclonal antibody designed to treat rare and severe complement-mediated disorders. Ravulizumab is an improved version of its predecessor, eculizumab, offering a longer half-life and reduced dosing frequency.

Key features of Ravulizumab include:

  • Molecular weight: Approximately 148 kDa
  • Structure: Humanized monoclonal antibody with an engineered Fc region
  • Target: Complement protein C5
  • Half-life: Approximately 49.7 days
  • Dosing interval: Every 8 weeks for most adult patients

Ravulizumab was first approved by the FDA in December 2018 for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH). Subsequent approvals have expanded its use to pediatric patients and other indications.

Mechanism of Action

Ravulizumab works by targeting the complement system, a part of the innate immune system. Specifically, it:

  1. Binds with high affinity and specificity to the complement protein C5
  2. Inhibits the cleavage of C5 into C5a (a potent anaphylatoxin) and C5b
  3. Prevents the formation of the terminal complement complex C5b-9 (also known as the membrane attack complex or MAC)

This mechanism effectively blocks the complement-mediated destruction of red blood cells in conditions like paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS).

In PNH, ravulizumab prevents intravascular hemolysis by inhibiting the formation of the MAC on PNH red blood cells. In aHUS, it prevents complement-mediated thrombotic microangiopathy (TMA) by inhibiting complement-mediated endothelial damage and platelet activation.

The engineered Fc portion of ravulizumab interacts with the neonatal Fc receptor (FcRn), which contributes to its extended half-life compared to eculizumab. This interaction allows for recycling of the antibody and reduces its clearance from the circulation.

Indications

Ravulizumab is FDA-approved for the following indications:

  1. Paroxysmal Nocturnal Hemoglobinuria (PNH):
    • Treatment of adult and pediatric patients one month of age and older
    • Used to reduce hemolysis and associated symptoms in patients with PNH
  2. Atypical Hemolytic Uremic Syndrome (aHUS):
    • Treatment of adult and pediatric patients one month of age and older
    • Used to inhibit complement-mediated thrombotic microangiopathy (TMA)
    • Not indicated for the treatment of Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS)
  3. Generalized Myasthenia Gravis (gMG):
    • Treatment of adult patients who are anti-acetylcholine receptor (AChR) antibody-positive
    • Used to improve muscle strength and reduce disability in patients with refractory gMG

It's important to note that ravulizumab is used as a long-term therapy in these chronic conditions. The decision to initiate treatment should be based on a comprehensive clinical evaluation and confirmed diagnosis.

Pharmacokinetics

Understanding the pharmacokinetics of ravulizumab is crucial for optimal dosing and therapeutic management:

  • Absorption: Ravulizumab is administered intravenously, resulting in 100% bioavailability.
  • Distribution:
    • Volume of distribution: Approximately 5.4 L
    • Primarily distributed in the vascular compartment
  • Metabolism:
    • As a protein, ravulizumab is expected to be metabolized into small peptides and amino acids through catabolic pathways
    • Not metabolized by cytochrome P450 enzymes
  • Elimination:
    • Half-life: Approximately 49.7 days
    • Clearance: Approximately 0.08 L/day
  • Special Populations:
    • No significant differences in pharmacokinetics based on age, sex, or race
    • Not significantly affected by renal or hepatic impairment

The extended half-life of ravulizumab compared to eculizumab is due to its engineered Fc region, which enhances recycling through the neonatal Fc receptor (FcRn). This allows for the 8-week dosing interval in most adult patients.

Dosage and Administration

Ravulizumab is administered as an intravenous infusion. The dosing regimen consists of a loading dose followed by maintenance doses:

Adult Dosing (≥ 40 kg):

  • Loading dose: 2,400 mg to 3,000 mg (based on body weight)
  • Maintenance dose: 3,000 mg to 3,600 mg every 8 weeks, starting 2 weeks after the loading dose

Pediatric Dosing (< 40 kg):

  • Loading dose: 600 mg to 2,400 mg (based on body weight)
  • Maintenance dose: 300 mg to 3,000 mg every 4 or 8 weeks (based on body weight), starting 2 weeks after the loading dose

Administration:

  1. Dilute ravulizumab in 0.9% sodium chloride injection or 5% dextrose in water
  2. Administer as an intravenous infusion over approximately 2 hours in adults and 1-4 hours in pediatric patients
  3. Use an in-line filter (0.2 or 0.22 micron pore size) during administration

Dosage adjustments may be necessary for patients switching from eculizumab to ravulizumab. Always refer to the most current prescribing information for exact dosing guidelines.

Adverse Effects

While ravulizumab is generally well-tolerated, it's important to be aware of potential adverse effects:

Common Adverse Effects (≥ 10% of patients):

  • Upper respiratory tract infections
  • Headache
  • Diarrhea
  • Nausea
  • Pyrexia (fever)
  • Pain in extremities
  • Abdominal pain
  • Dizziness
  • Arthralgia (joint pain)

Serious Adverse Effects:

  • Meningococcal infections (boxed warning): Life-threatening and fatal meningococcal infections have occurred in patients treated with ravulizumab
  • Other serious infections: Patients may have increased susceptibility to encapsulated bacteria infections
  • Infusion-related reactions: Including hypersensitivity reactions

Laboratory Abnormalities:

  • Decreased neutrophil counts
  • Increased serum creatinine levels

It's crucial to educate patients about the signs and symptoms of meningococcal infection and advise them to seek immediate medical attention if these symptoms occur. Healthcare providers should monitor patients closely for any signs of infection or other adverse effects throughout treatment.

Monitoring and Precautions

Due to the nature of ravulizumab and its effects on the immune system, careful monitoring and several precautions are necessary:

Pre-treatment Requirements:

  • Vaccinations: Patients must be vaccinated against meningococcal infections at least 2 weeks prior to receiving the first dose of ravulizumab
    • If urgent therapy is indicated, administer meningococcal vaccines as soon as possible and provide patients with 2 weeks of antibacterial drug prophylaxis
  • Pregnancy Test: For women of childbearing potential

Ongoing Monitoring:

  • Meningococcal infection: Monitor for signs and symptoms and evaluate immediately if suspected
  • Complement inhibition: Assess through monitoring of LDH levels
  • Hematological parameters: Regular complete blood counts
  • Renal function: Monitor serum creatinine and estimated glomerular filtration rate (eGFR)
  • Hepatic function: Monitor liver enzymes periodically
  • Infusion reactions: Monitor patients during infusion and for at least one hour after completion

Additional Precautions:

  • Immunizations: Live vaccines should be avoided during treatment
  • Discontinuation: May result in rapid return of disease symptoms; close monitoring is required if treatment is interrupted or discontinued
  • Pregnancy: May cause fetal harm; effective contraception should be used during treatment and for 8 months after the last dose
  • Lactation: Advise women not to breastfeed during treatment and for 8 months after the last dose

Healthcare providers should maintain a high index of suspicion for meningococcal infections and other serious infections in patients receiving ravulizumab. Patient education about the risks and necessary precautions is crucial for safe and effective treatment.



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