What is the risk of hepatotoxicity associated with voriconazole?

Hepatotoxicity Risk Associated with Voriconazole

Mild hepatotoxicity is common with voriconazole use and is related to drug concentration, while severe hepatotoxicity is uncommon. 1

Incidence and Severity

Voriconazole-associated hepatotoxicity typically manifests as elevated serum bilirubin, alkaline phosphatase, and hepatic aminotransferase enzyme levels. The risk profile includes:

• Mild hepatotoxicity is common with all azoles and related to drug concentration 1
• Hepatotoxicity occurs in approximately 19-51% of patients receiving voriconazole 2, 3
• Severe hepatotoxicity requiring discontinuation occurs in approximately 34% of patients 3
• Hepatotoxicity typically develops early, with a median time to onset of 3 days (range 1-24 days) 4
• 83.2% of hepatotoxicity cases occur within the first 7 days of voriconazole initiation 4

Risk Factors for Voriconazole Hepatotoxicity

Several factors increase the risk of developing hepatotoxicity:

1. Plasma Concentration:

   • Trough concentrations >3.42 mg/L significantly increase risk of grade ≥2 hepatotoxicity 4
   • Trough concentrations >4 mg/L are associated with higher hepatotoxicity risk 2, 5
   • Trough concentrations >6.87 mg/L significantly increase risk of grade ≥3 (severe) hepatotoxicity 4
   • Sustained high trough concentrations (>4 μg/ml in consecutive measurements) dramatically increase hepatotoxicity risk (83.3% vs 16-25% in patients with lower levels) 5

2. Patient-Specific Factors:

   • Acute graft-versus-host disease in HSCT recipients 6
   • Age less than 40 years 3
   • History of liver disease 3
   • Cystic fibrosis 3
   • Perioperative initiation of voriconazole (within 30 days of transplantation) increases risk 4.37-fold 3
   • Septic shock 4

3. Medication-Related Factors:

   • Concomitant use of hepatotoxic drugs, particularly:
     • Trimethoprim-sulfamethoxazole 4
     • Tigecycline 4
     • Azathioprine 3
     • Use of three or more hepatotoxic drugs simultaneously 4

Monitoring and Management

To minimize hepatotoxicity risk:

1. Therapeutic Drug Monitoring (TDM):

   • TDM is strongly recommended for voriconazole therapy 1
   • Monitor trough concentrations early (as soon as steady state is achieved) 4
   • Target trough concentrations between 1-1.5 μg/mL for efficacy and <4-5 μg/mL to minimize toxicity 1, 2, 5

2. Liver Function Monitoring:

   • Measure hepatic enzymes before starting therapy 1
   • Monitor at 2 and 4 weeks after therapy initiation 1
   • Continue monitoring every 3 months during therapy 1

3. Dose Adjustment:

   • If trough concentrations exceed 4 μg/mL, consider dose reduction 5
   • Decreasing trough concentration to <4 μg/mL after initial high readings may reduce hepatotoxicity incidence 5

Special Populations

Certain patient populations require special consideration:

1. Transplant Recipients:

   • 34% of HSCT recipients develop hepatotoxicity while on voriconazole 6
   • In lung transplant recipients, perioperative initiation carries significantly higher risk 3
   • Consider delaying voriconazole initiation beyond 30 days post-transplant when possible 3

2. ICU Patients:

   • Critically ill patients show large interindividual variability in voriconazole concentrations 4
   • Higher vigilance needed in patients with septic shock or multiple hepatotoxic medications 4

Clinical Implications

Despite the risk of hepatotoxicity, voriconazole remains a valuable antifungal agent:

• Hepatic dysfunction is generally mild and reversible 6
• No cases of liver failure or death attributed to voriconazole were reported in HSCT recipients 6
• Benefits often outweigh risks in patients at high risk for invasive fungal infections 6

When hepatotoxicity occurs, discontinuation of voriconazole and switching to an alternative antifungal agent may be necessary, particularly in cases of severe hepatotoxicity.