What are the considerations for using Nintedanib (Bosentan) in patients with Interstitial Lung Disease (ILD) and Chronic Kidney Disease (CKD)?

Nintedanib in Interstitial Lung Disease with Chronic Kidney Disease

Nintedanib can be used in patients with ILD and CKD with careful monitoring of renal function, as there is evidence of safety even in advanced kidney disease, though dose adjustment may be necessary in severe cases.

Efficacy of Nintedanib in ILD

• Nintedanib is an intracellular inhibitor of multiple tyrosine kinases that targets growth factor receptors including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) 1
• In progressive pulmonary fibrosis (PPF), nintedanib significantly reduces the annual rate of forced vital capacity (FVC) decline by approximately 107 ml compared to placebo 2
• The efficacy varies by underlying disease type, with greater FVC preservation in CTD-related ILD (106.2 ml/yr), fibrotic NSIP (141.7 ml/yr), and fibrotic occupational lung disease (252.8 ml/yr) 2
• Nintedanib decreases the risk of ILD progression 2.4 times in patients with progressive pulmonary fibrosis 2
• The drug has shown efficacy even in advanced IPF (FVC < 50% predicted), with significant improvement in FVC decline rate after treatment (-0.77% vs. -0.22% predicted/month, p=0.003) 3

Nintedanib in CKD Patients

• The safety and pharmacokinetics of nintedanib have not been extensively studied in patients with severe renal impairment (creatinine clearance < 30 mL/min) 4
• Recent case reports suggest nintedanib may be tolerated in patients with advanced kidney disease, including those requiring hemodialysis, with careful monitoring 4
• No specific toxic effects were observed in a patient with IPF who continued nintedanib therapy even when requiring hemodialysis 4
• The standard dose of nintedanib is 150mg twice daily, but dose reduction to 100mg twice daily should be considered if not tolerated in patients with renal impairment 5

Adverse Effects and Management

• Gastrointestinal effects are most common with nintedanib treatment: 2, 1

  • Diarrhea (2.8 times more frequent than placebo)
  • Abdominal pain (4.2 times more frequent)
  • Nausea (3.1 times more frequent)
  • Vomiting (3.6 times more frequent)
  • Anorexia (2.8 times more frequent)
  • Weight loss (3.7 times more frequent)

• Liver enzyme elevations are also common: 2

  • Elevated aspartate aminotransferase (3.2 times more frequent)
  • Elevated alanine aminotransferase (3.6 times more frequent)

• Nintedanib increases the likelihood of: 2

  • Any adverse event (1.1 times more frequent)
  • Adverse events leading to permanent dose reduction (7.9 times more frequent)
  • Adverse events leading to treatment discontinuation (1.9 times more frequent)

• For persistent diarrhea or other significant adverse effects, temporary dose reduction to 100 mg twice daily or treatment interruption may be necessary 1, 5

Monitoring Recommendations for ILD Patients with CKD

• Regular monitoring of renal function is essential when using nintedanib in patients with CKD 4
• Liver function tests should be performed regularly as nintedanib can cause elevations in liver enzymes 2, 5
• Monitor for gastrointestinal symptoms, particularly diarrhea, which may require dose adjustment or supportive management 1, 5
• Assess respiratory status regularly, as treatment interruption due to adverse effects may lead to worsening of respiratory function 4, 3
• In patients with advanced ILD and CKD, the risk-benefit ratio should be carefully evaluated, as these patients may have a higher frequency of treatment interruption (68.0% vs. 40.0% in non-advanced disease) 3

Treatment Algorithm for ILD with CKD

1. Confirm ILD diagnosis and assess severity (FVC, DLCO, radiological pattern) 2
2. Evaluate renal function (creatinine clearance) 4
3. For patients with mild to moderate CKD (creatinine clearance > 30 mL/min):
   • Start nintedanib at standard dose of 150 mg twice daily 1, 5
4. For patients with severe CKD (creatinine clearance < 30 mL/min):
   • Consider starting at reduced dose of 100 mg twice daily with careful monitoring 5, 4
5. Monitor for adverse effects, particularly:
   • Gastrointestinal symptoms (diarrhea, nausea, vomiting) 2
   • Liver enzyme elevations 2
   • Changes in renal function 4
6. Adjust dose based on tolerability:
   • For persistent adverse effects, reduce dose to 100 mg twice daily 1, 5
   • If adverse effects continue, consider temporary interruption 1, 5
7. Reassess efficacy and safety regularly:
   • Pulmonary function tests every 3-6 months 3
   • Renal function and liver enzymes every 1-3 months 4

Important Considerations and Pitfalls

• Nintedanib slows disease progression but does not reverse existing fibrosis 5
• The risk of treatment discontinuation is higher in patients with advanced disease, mainly due to disease progression (47.1% vs. 36.4%) 3
• There is no evidence of increased bleeding risk in patients taking concomitant anticoagulant therapy with nintedanib 6
• For most patients with chronic fibrosing ILDs, the 150 mg nintedanib twice daily dose provides exposure levels associated with a therapeutic effect close to the maximum nintedanib effect 7
• The quality of evidence for nintedanib in PPF is rated as low to moderate, meaning that the committee had low confidence in the estimated effects 2