What are the considerations for using Nintedanib (BIBF 1120) in patients with liver failure?

Nintedanib in Liver Failure Patients: Contraindicated Due to High Risk

Nintedanib is contraindicated in patients with liver failure due to significantly increased drug exposure and risk of hepatotoxicity. 1 The medication should not be administered to patients with moderate to severe hepatic impairment (Child-Pugh B or C), as exposure can increase up to 8-fold compared to patients with normal liver function.

Pharmacokinetic Considerations

Nintedanib is primarily metabolized via hydrolytic ester cleavage and subsequently undergoes glucuronidation with fecal elimination 2. Key pharmacokinetic factors relevant to liver failure include:

• Exposure increases approximately 2-fold in mild hepatic impairment (Child-Pugh A) and 8-fold in moderate hepatic impairment (Child-Pugh B) 1
• Terminal elimination half-life is 10-15 hours in patients with normal liver function 2
• Less than 1% of drug-related radioactivity is eliminated through the kidneys 2
• Accumulation is negligible with twice-daily dosing in patients with normal liver function 2

Risk Assessment Framework

Absolute Contraindications:

• Moderate to severe hepatic impairment (Child-Pugh B or C)
• Acute liver failure
• Severe transaminase elevations (>5× ULN)

Relative Contraindications (requiring careful risk-benefit assessment):

• Mild hepatic impairment (Child-Pugh A)
• History of drug-induced liver injury
• Concomitant use of hepatotoxic medications

Monitoring Recommendations for Patients with Mild Hepatic Impairment

If treatment is deemed absolutely necessary in a patient with mild hepatic impairment (Child-Pugh A):

1. Start at reduced dose (100 mg twice daily instead of standard 150 mg twice daily) 3
2. Monitor liver function tests (LFTs) every month for first 3 months, then every 3 months 3
3. Be vigilant for signs of hepatotoxicity, including:
   • Elevated transaminases
   • Fatigue
   • Right upper quadrant pain
   • Jaundice

Special Considerations

Gender Differences

Women have a three to fourfold higher exposure-adjusted risk of liver enzyme elevations than men 4, which may further increase risk in female patients with liver impairment.

Ethnicity and Body Weight

Asian patients and those with low body weight (approximately 59 kg) appear to have higher risk of developing drug-induced liver injury with nintedanib 5.

Concomitant Medications

Avoid concomitant use of other hepatotoxic drugs, particularly:

• Statins
• Proton pump inhibitors
• Certain antibiotics 5

Management of Acute Liver Failure

For patients who develop acute liver failure, management should follow established protocols:

• Early contact with a transplant unit 3
• Systematic administration of N-acetylcysteine regardless of etiology 3
• Treatment of extrahepatic organ failure and prevention of aggravating factors 3
• Monitoring for encephalopathy, hemodynamic status, and renal function 3

Alternatives for Interstitial Lung Disease Treatment

For patients with interstitial lung disease who have liver failure, consider alternative agents:

• Mycophenolate (with dose adjustment and close monitoring) 3
• Rituximab (if appropriate for the underlying condition) 3
• Corticosteroids (short-term use) 3

In conclusion, the risks of nintedanib in liver failure significantly outweigh potential benefits due to dramatically increased drug exposure and hepatotoxicity risk. Alternative treatment options should be strongly considered for patients with underlying liver disease.