How should avacopan be initiated and the oral prednisone tapered in a patient currently receiving oral prednisone?

How to Initiate Avacopan in Patients Currently on Oral Steroids

Start avacopan 30 mg twice daily immediately while simultaneously beginning a rapid prednisone taper, aiming to discontinue prednisone completely by week 20-21. 1

Avacopan Dosing

• Initiate avacopan at 30 mg orally twice daily 2, 1
• Continue avacopan for the full 52-week treatment course 1
• Avacopan should be combined with standard immunosuppressive therapy (rituximab or cyclophosphamide) 2

Prednisone Tapering Strategy

When starting avacopan in a patient already on oral prednisone, use the PEXIVAS reduced-dose glucocorticoid taper regimen as your framework 2, 3:

Weight-Based Tapering Schedule (mg/day prednisolone equivalent):

• Week 1: 50 mg (<50 kg), 60 mg (50-75 kg), 75 mg (>75 kg) 2, 3
• Week 2: 25 mg (<50 kg), 30 mg (50-75 kg), 40 mg (>75 kg) 2, 3
• Weeks 3-4: 20 mg (<50 kg), 25 mg (50-75 kg), 30 mg (>75 kg) 2, 3
• Weeks 5-6: 15 mg (<50 kg), 20 mg (50-75 kg), 25 mg (>75 kg) 2, 3
• Continue tapering progressively to 5 mg by weeks 19-20 2, 3
• Discontinue prednisone completely by week 20-21 3, 1

Key Tapering Principles:

If the patient is currently on a higher prednisone dose than the week 1 target, you can either:

1. Rapidly taper to the week 1 dose over 3-5 days, then follow the schedule above 2
2. Start the taper from their current dose if already within the schedule range 2

The goal is complete glucocorticoid withdrawal by week 20-21, which was the protocol used in the ADVOCATE trial that demonstrated avacopan's efficacy 1, 4

Clinical Context and Evidence

The ADVOCATE trial established that avacopan can effectively replace glucocorticoids in AAV treatment, with patients receiving approximately 2500 mg less cumulative prednisone over 52 weeks compared to standard taper 4, 5. This resulted in:

• Superior sustained remission at week 52 (65.7% vs 54.9%) 1, 4
• Significantly reduced glucocorticoid toxicity across multiple domains (BMI, glucose tolerance, lipid metabolism, skin toxicity) by week 13 and 26 6
• Better renal outcomes, particularly in patients with eGFR <20 ml/min/1.73 m² 2, 7
• Improved health-related quality of life at both 26 and 52 weeks 5

Patient Selection Considerations

Avacopan is particularly beneficial for patients with: 2

• Increased risk of glucocorticoid toxicity (diabetes, osteoporosis, obesity) 2
• Active glomerulonephritis with lower GFR (especially <20 ml/min/1.73 m²) 2, 7
• Age ≥65 years (demonstrated similar efficacy with reduced steroid burden) 8

Important exclusions from trial data: 2, 3

• eGFR <15 ml/min/1.73 m² 2, 3
• Alveolar hemorrhage requiring mechanical ventilation 2, 3
• However, emerging case reports suggest potential benefit even in severe pulmonary hemorrhage 9

Critical Monitoring Points

• Glucocorticoids may still be needed for: 1

  • Rituximab premedication (to reduce hypersensitivity reactions) 1
  • Treatment of persistent or worsening vasculitis 1
  • Relapses during the treatment course 1
  • Adrenal insufficiency management 1

• Drug interactions: Avacopan shows time-dependent inhibition and induction of CYP3A4, which may affect sensitive CYP3A4 substrates (e.g., simvastatin exposure increased 3.5-fold) 1

• Safety profile: Serious adverse events were comparable between avacopan (37.3%) and prednisone taper (39.0%) groups, with no increased infection risk 4, 7

Practical Implementation

Start both medications simultaneously rather than waiting to taper steroids first. The ADVOCATE trial protocol initiated avacopan at the same time as beginning the prednisone taper, demonstrating this approach is both safe and effective 1, 4. This allows for immediate reduction in glucocorticoid exposure while maintaining disease control through complement inhibition 2.