Can eltrombopag cause deranged liver function?

Can Eltrombopag Cause Deranged Liver Function?

Yes, eltrombopag definitively causes hepatobiliary laboratory abnormalities and hepatotoxicity, with increased alanine aminotransferase (ALT) being one of the most common adverse events occurring in approximately 5-13% of patients. 1, 2

Incidence and Severity of Liver Dysfunction

Liver dysfunction occurs in approximately 22.4% of patients treated with eltrombopag, with the following patterns: 3

• Elevated ALT in 11.8% of patients 3
• Elevated total bilirubin (TBIL) in 12.9% of patients 3
• Drug-induced hepatocellular injury in 8.2% of cases 3

The severity distribution is typically mild to moderate: 3

• Grade 1 (mild): 73.7% of cases
• Grade 2 (moderate): 15.8% of cases
• Grade 3 (severe): 10.5% of cases

Clinical Presentation

The FDA label specifically lists "increased ALT" as one of the most common adverse events (≥5% and greater than placebo) in clinical trials. 2 In controlled trials: 2

• Serum liver test abnormalities (predominantly Grade 2 or less) occurred in 11% of eltrombopag-treated patients versus 7% of placebo patients 2
• 1% of patients discontinued treatment due to hepatobiliary laboratory abnormalities 2
• Hepatotoxicity can range from asymptomatic transaminase elevations to acute liver failure 4

High-Risk Populations Requiring Caution

Eltrombopag should be used with extreme caution in patients with preexisting liver disease, with close monitoring of liver function tests. 1 Specific high-risk groups include: 3, 5

• Patients with type 2 diabetes (significantly correlated with liver dysfunction, P=0.04) 3
• Patients with noninflammatory hepatobiliary disease including gallbladder stones, gallbladder polyps, liver cysts, or fatty liver (P=0.023) 3
• Patients with moderate or severe hepatic impairment (93% and 80% increases in drug exposure, respectively) 5

Dosing Adjustments for Hepatic Impairment

Patients with moderate or severe hepatic impairment should initiate eltrombopag at a reduced dose of 25 mg once daily (rather than the standard 50 mg) due to significantly increased drug exposure. 5 The pharmacokinetic data show: 5

• Mild hepatic impairment: 41% increase in AUC
• Moderate hepatic impairment: 93% increase in AUC
• Severe hepatic impairment: 80% increase in AUC

Monitoring Requirements

Close monitoring of liver function tests is mandatory during eltrombopag therapy. 1 The monitoring strategy should include: 2, 3

• Baseline liver function tests before initiating therapy 2
• Regular monitoring during treatment, with increased frequency in high-risk patients 3
• Immediate evaluation if clinical signs of hepatotoxicity develop 4

Management of Liver Dysfunction

When hepatobiliary abnormalities occur, treatment interruption typically results in reversibility. 2 The clinical approach includes: 2

• Discontinuation in patients with Grade 3 or higher liver test abnormalities 2
• Re-challenge may be considered after resolution, though recurrence is common (8 of 17 patients experienced recurrent abnormalities upon re-exposure) 2
• Permanent discontinuation if severe hepatotoxicity develops 4

Important Caveats

Despite concerns about hepatotoxicity, long-term administration studies have shown stable liver function in some patient populations. 6 However, this does not negate the need for vigilance, as: 4

• Acute liver failure has been reported, even with standard dosing 4
• Pharmacogenetic variations in CYP2C8, UGT1A1, and ABCG2 may predispose certain patients to toxicity 4
• Therapeutic drug monitoring is not routinely performed but may be valuable in patients with unexpected complications 4

The risk-benefit assessment must account for the indication: while hepatotoxicity is a concern in immune thrombocytopenia patients, eltrombopag has an obsolete indication for hepatitis C-related thrombocytopenia and is not recommended for routine pre-procedural use in chronic liver disease due to excess thrombotic events. 7