What are the clinical uses and dosing guidelines for Voclosporin (Cyclosporin analog) in patients?

Clinical Uses and Dosing Guidelines for Voclosporin in Patients

Voclosporin is primarily indicated for the treatment of adults with active lupus nephritis (LN) in combination with mycophenolate mofetil (MMF) and low-dose glucocorticoids in patients with baseline eGFR of at least 45 mL/min/1.73 m². 1

Primary Indication: Lupus Nephritis

Efficacy in Lupus Nephritis

• Voclosporin was FDA approved following positive results from two clinical trials:
  • Phase 2b AURA-LV trial: Complete remission rates at 6 months were significantly higher with voclosporin (32.6% vs 19.3%; p=0.049)
  • Phase 3 AURORA-1 trial: Complete remission rates at 12 months were significantly higher with voclosporin (41% vs 23%; p<0.0001) 1
• Long-term data from AURORA-2 showed sustained efficacy with mean UPCR at 30 months of 0.58 mg/g in the voclosporin arm vs 1.34 g/g in the control arm 1, 2

Standard Dosing Guidelines

• Recommended dose: 23.7 mg twice daily 1, 3
• Duration: Initially approved for 1 year of treatment 1
• Long-term treatment (up to 3 years) has shown continued efficacy and acceptable safety profile 2

Patient Selection Criteria

• Adults with active LN (Class III, IV, or V alone or in combination)
• Baseline eGFR must be ≥45 mL/min/1.73 m² (patients with lower eGFR were excluded from clinical trials) 1
• Used in combination with MMF (target dose 2 g/day) and reduced steroid regimen 1, 4

Dosing Considerations in Special Populations

Renal Impairment

• No dose adjustment needed for mild to moderate renal impairment 5
• Severe renal impairment (CrCl <30 mL/min) results in 1.5-fold increase in AUC without increase in Cmax 5
• Not recommended in patients with baseline eGFR <45 mL/min/1.73 m² (excluded from clinical trials) 1, 3
• Monitor eGFR closely, especially in first 3 months of treatment 3

Hepatic Impairment

• Mild to moderate hepatic impairment results in 1.5-2.0 fold increase in exposure 3, 5
• Appropriate monitoring recommended for patients with hepatic impairment 5
• Effect of severe hepatic impairment (Child-Pugh C) is unknown 3

Drug Interactions

Important Drug Interactions

• Strong CYP3A4 inhibitors (e.g., ketoconazole): Increase voclosporin exposure 18-fold; concomitant use should be avoided 3, 6
• Moderate CYP3A4 inhibitors: Predicted to increase voclosporin exposure approximately 2-3 fold 3
• Strong CYP3A4 inducers (e.g., rifampin): Decrease voclosporin exposure by 87%; concomitant use should be avoided 3, 6
• P-glycoprotein inhibitors (e.g., verapamil): Increase voclosporin exposure 2.7-fold; monitoring recommended 6
• P-glycoprotein substrates (e.g., digoxin): Voclosporin increases exposure; monitoring recommended 3, 6

Monitoring and Safety Considerations

Key Monitoring Parameters

1. Renal function:

   • Monitor eGFR frequently, especially in first 3 months
   • 71% of decreases in GFR occur within first 3 months of treatment
   • 78% resolved or improved following dose modification 3

2. Blood pressure:

   • Hypertension reported in 25.2 per 100 patient-years with voclosporin vs 10.3 with placebo 3
   • Regular blood pressure monitoring recommended

3. Infections:

   • Infections reported in 135.2 per 100 patient-years with voclosporin vs 107.4 with placebo 3
   • Monitor for signs of infection, particularly upper respiratory tract infections and urinary tract infections

Common Adverse Effects

• Decreased GFR (most frequent adverse reaction)
• Hypertension
• Headache, tremor, dizziness (neurological effects)
• Infections (upper respiratory tract, urinary tract)
• Gastrointestinal symptoms 3

Clinical Pearls and Caveats

• Voclosporin is a novel CNI modified from cyclosporine A with more consistent pharmacokinetic and pharmacodynamic predictability 1
• Unlike other CNIs, voclosporin does not require therapeutic drug monitoring 7
• Reduction in proteinuria may be partly due to non-immunosuppressive effects (decreased glomerular filtration pressure, stabilization of podocyte cytoskeleton) 1
• A small increase in proteinuria may occur after voclosporin withdrawal, consistent with CNI discontinuation 1
• The benefit of voclosporin appears less pronounced in patients receiving MMF >2 g/day 1
• Long-term safety data from AURORA-2 shows stable eGFR over 3 years of treatment 2

Voclosporin represents an important advancement in LN treatment, offering improved complete renal response rates with an acceptable safety profile when used in appropriate patients with adequate renal function.