What is the impact of Cabozantinib (generic name: Cabozantinib) on liver function?

Impact of Cabozantinib on Liver Function

Cabozantinib requires careful monitoring of liver function as it can cause hepatotoxicity, with higher risk in patients with pre-existing liver impairment, particularly those with moderate (Child-Pugh B) hepatic dysfunction who require dose reduction. 1

Pharmacokinetics and Liver Metabolism

• Cabozantinib is primarily metabolized by the liver through CYP3A4 enzymes and is highly protein-bound (≥99.7%) in human plasma 1
• Approximately 54% of the drug is recovered in feces, with 43% as unchanged cabozantinib, indicating significant hepatic processing 1
• Cabozantinib exposure (AUC) increases by 63% in patients with moderate hepatic impairment (Child-Pugh B), necessitating dose reduction 1
• Population pharmacokinetic studies show minimal differences in cabozantinib clearance for patients with mild liver dysfunction compared to those with normal liver function 2

Clinical Use in Hepatocellular Carcinoma

• The AGA recommends cabozantinib for patients with advanced HCC and preserved liver function (Child-Pugh A) who have progressed on sorafenib, with a conditional recommendation based on very low certainty evidence 3
• In the CELESTIAL trial, cabozantinib improved overall survival (10.2 vs 8.0 months) compared to placebo in patients with HCC who progressed on sorafenib 3
• Almost all patients (99%) in the CELESTIAL trial had preserved liver function (Child-Pugh A), limiting data on safety in more advanced liver disease 3
• Real-world data shows median OS of 9.7 months in Child-Pugh A patients but only 3.4 months in Child-Pugh B patients, suggesting poorer outcomes with impaired liver function 4

Safety and Adverse Events Related to Liver

• Significantly higher rates of serious adverse events were observed with cabozantinib compared to placebo (49.7% vs 21%) in the CELESTIAL trial 3
• Treatment discontinuation due to adverse events was higher in the cabozantinib group (21% vs 4.6%) 3
• Dose reductions may be beneficial for patients with impaired liver function, with lower discontinuation rates (42.9% vs 75.0%) when starting at 40 or 20 mg versus 60 mg 5
• Cabozantinib has not been studied in patients with severe hepatic impairment (Child-Pugh C) and should be avoided in this population 1

Monitoring and Management Recommendations

• Regular liver function monitoring is essential during cabozantinib treatment 1
• For patients with moderate hepatic impairment (Child-Pugh B), dose reduction is required 1
• Patients with severe hepatic impairment (Child-Pugh C) should not receive cabozantinib 1
• Managing adverse events through dose reduction may extend treatment duration with cabozantinib 5
• Consider alternative therapies such as pembrolizumab for patients with HCC who have progressed on sorafenib, especially those with significant liver dysfunction 3

Cabozantinib in Special Liver-Related Populations

• Limited data exists for cabozantinib use in liver transplant recipients with recurrent HCC, though ongoing trials are evaluating its efficacy and safety in this population 6
• In real-world practice, cabozantinib is increasingly used in later lines of therapy (4th line or beyond) and in patients with Child-Pugh B liver function, populations not well-represented in clinical trials 5, 4

Comparative Liver Safety Profile

• Among second-line therapies for HCC, cabozantinib has a higher rate of adverse events compared to placebo but shows significant survival benefit 3
• Other options like regorafenib and ramucirumab have their own safety profiles, with regorafenib requiring prior tolerance to sorafenib 3
• The ESMO guidelines rate cabozantinib with an ESMO-MCBS score of 3, reflecting its efficacy-to-toxicity balance 3