What is the role of Nintedanib (BIBF 1120) in treating Interstitial Lung Disease (ILD) with concurrent Chronic Liver Disease (CLD)?

Role of Nintedanib in ILD with Concurrent Chronic Liver Disease

Nintedanib should be used with extreme caution in patients with ILD who have concurrent chronic liver disease, with close monitoring of liver function and consideration of alternative therapies when possible. 1

Indications for Nintedanib in Different ILD Types

• Nintedanib is conditionally recommended as a first-line treatment option for systemic sclerosis-associated ILD (SSc-ILD), where it has demonstrated efficacy in slowing the rate of forced vital capacity (FVC) decline 2
• For rheumatoid arthritis-associated ILD (RA-ILD), there was no consensus among experts on nintedanib as first-line therapy, though some specialists consider it for patients with a fibrotic/UIP pattern 2
• Nintedanib is conditionally recommended against as a first-line option for Sjögren's disease-ILD, idiopathic inflammatory myopathies-ILD, and mixed connective tissue disease-ILD 2
• For patients with SARD-ILD progression despite first-line treatment, nintedanib is conditionally recommended as a treatment option regardless of the underlying disease 2

Efficacy and Mechanism

• Nintedanib is a tyrosine kinase inhibitor that slows the rate of decline in FVC in patients with various fibrosing ILDs 3, 4
• In the SENSCIS trial, nintedanib reduced the annual rate of FVC decline to -52.4 mL/year compared to -93.3 mL/year with placebo (p=0.04) in SSc-ILD patients 3
• In the INBUILD trial, nintedanib demonstrated efficacy in reducing FVC decline across various progressive fibrosing ILDs, including autoimmune disease-related ILDs 3, 5
• Nintedanib slows disease progression but does not reverse existing fibrosis or affect non-ILD manifestations of systemic autoimmune rheumatic diseases 3

Liver Concerns and Monitoring

• Nintedanib is associated with hepatotoxicity, requiring regular monitoring of liver function tests 1, 3
• The American College of Rheumatology recommends monitoring liver function tests monthly for the first 3 months of nintedanib therapy, then every 3 months thereafter 1
• There is a positive correlation between nintedanib exposure and risk of liver enzyme elevations, which is consistent across studies in IPF, SSc-ILD, and progressing fibrosing ILDs 6
• Female patients have a three to fourfold higher exposure-adjusted risk of liver enzyme elevations than males 6
• For patients with pre-existing chronic liver disease, the additional hepatotoxic potential of nintedanib poses significant concerns 1

Dosing Considerations in Liver Disease

• The standard dose of nintedanib is 150mg twice daily, but can be reduced to 100mg twice daily if not tolerated 3
• Dose adjustments may be necessary in patients with liver disease to balance efficacy and safety 1
• For patients with mild hepatic impairment (Child Pugh A), close monitoring is recommended 1
• Nintedanib should be used with extreme caution or avoided in patients with moderate to severe hepatic impairment 1

Management of Adverse Effects

• Diarrhea is the most common adverse event (75.7% of patients), followed by nausea, vomiting, abdominal pain, anorexia, and weight loss 3, 7
• Management strategies for adverse effects include:
  • Dose reduction to 100mg twice daily if not tolerated 3
  • Treatment interruptions to manage severe side effects 7
  • Use of anti-diarrheal medications 7
  • Regular monitoring of liver enzymes, particularly in the first few months of treatment 1, 7

Treatment Algorithm for ILD with CLD

1. Assessment of liver function and ILD severity:

   • Evaluate baseline liver function tests and Child-Pugh classification 1
   • Determine ILD pattern (UIP vs non-UIP) and progression rate 3

2. Treatment selection based on ILD type and liver status:

   • For SSc-ILD with mild liver impairment: Consider nintedanib with close monitoring 2, 1
   • For RA-ILD with fibrotic/UIP pattern and mild liver impairment: Consider nintedanib with close monitoring 2
   • For other SARD-ILDs or moderate-severe liver impairment: Consider alternative immunosuppressive therapies 2, 1

3. Monitoring protocol:

   • Monthly liver function tests for first 3 months, then every 3 months 1
   • More frequent monitoring for patients with pre-existing liver disease 1
   • Regular assessment of FVC and symptoms 4

4. Dose adjustment strategy:

   • Start at lower dose (100mg twice daily) in patients with mild liver impairment 1, 3
   • Temporary interruption for significant liver enzyme elevations 1
   • Permanent discontinuation for severe liver injury 1

Alternative Therapies for ILD with CLD

• Mycophenolate is conditionally recommended as a first-line ILD treatment option and may have a better safety profile in patients with liver disease 2
• Rituximab is conditionally recommended as both a first-line and second-line option for SARD-ILD 2
• For SSc-ILD and MCTD-ILD, tocilizumab is conditionally recommended as a first-line treatment option 2
• For patients with IIM-ILD, JAK inhibitors and calcineurin inhibitors are conditionally recommended as first-line options 2