What to do with pazopanib (pazopanib) when bilirubin is elevated to 2 times the upper limit of normal (ULN) with normal alanine transaminase (ALT) levels at week 6?

Management of Pazopanib with Isolated Bilirubin Elevation (2× ULN) and Normal ALT at Week 6

Hold pazopanib immediately and repeat liver function tests within 48-72 hours, as isolated bilirubin elevation ≥2× ULN during pazopanib therapy requires drug interruption regardless of normal ALT. 1

Immediate Actions

• Interrupt pazopanib now – do not wait for repeat testing to hold the drug 1
• Repeat complete liver panel (ALT, AST, alkaline phosphatase, total and direct bilirubin) within 48-72 hours to confirm the elevation and assess trajectory 2
• Assess for hepatic symptoms: severe fatigue, nausea, vomiting, right upper quadrant pain, jaundice, pruritus, or abdominal distention 2
• Check INR to evaluate synthetic liver function 3
• Obtain direct (conjugated) bilirubin to differentiate hepatocellular injury from cholestatic patterns 2

Differential Diagnosis Workup

While pazopanib is held, evaluate for alternative causes of hyperbilirubinemia:

• Rule out Gilbert's syndrome – if isolated unconjugated (indirect) hyperbilirubinemia with normal ALT, this benign condition may be unmasked by pazopanib but does not require permanent discontinuation 1
• Check viral hepatitis serologies (HBsAg, anti-HBc, anti-HCV) if not recently done 3
• Review all concomitant medications for hepatotoxic agents 3
• Obtain abdominal ultrasound to exclude biliary obstruction, progression of liver metastases, or structural abnormalities 3
• Consider hemolysis workup (LDH, haptoglobin, reticulocyte count) if indirect hyperbilirubinemia predominates 3

Decision Algorithm for Pazopanib Resumption

If bilirubin elevation is confirmed on repeat testing:

Scenario 1: Isolated Unconjugated Hyperbilirubinemia (Gilbert's Syndrome Pattern)

• If direct bilirubin remains normal and total bilirubin elevation is mild, consider Gilbert's syndrome 1
• May resume pazopanib at same dose with weekly liver function monitoring for 8 weeks 1
• This is the only scenario where bilirubin ≥2× ULN does not mandate permanent discontinuation 1

Scenario 2: Conjugated Hyperbilirubinemia or Mixed Pattern

• If direct bilirubin is elevated (>2× baseline and baseline >0.5 mg/dL), this suggests hepatocellular or cholestatic injury 2
• Permanently discontinue pazopanib if bilirubin remains >2× ULN on repeat testing 1
• Continue monitoring liver function tests until complete resolution to baseline 2

Scenario 3: Bilirubin Improves to <2× ULN on Repeat Testing

• If bilirubin decreases below 2× ULN and ALT remains normal, another etiology may be responsible 2
• May consider rechallenge only if alternative explanation is identified (e.g., transient biliary obstruction, hemolysis, drug interaction) 2
• Resume at reduced dose of 400 mg once daily (not 800 mg) with weekly liver function monitoring for 8 weeks 1
• Permanently discontinue if bilirubin elevation >2× ULN recurs 1

Critical Monitoring if Pazopanib is Resumed

• Measure liver function tests weekly for 8 weeks after resumption 1
• Permanently discontinue if any of the following occur 1:
  • ALT >3× ULN with concurrent bilirubin >2× ULN (Hy's Law criteria)
  • ALT >8× ULN even with normal bilirubin
  • Recurrence of bilirubin >2× ULN
  • Development of hepatic symptoms

Common Pitfalls to Avoid

• Do not continue pazopanib while awaiting repeat testing – the FDA label mandates immediate interruption for bilirubin elevations, unlike isolated ALT elevations which may be monitored 1
• Do not assume this is benign fluctuation – isolated bilirubin elevation at week 6 is within the high-risk window for pazopanib hepatotoxicity (most cases occur in first 18 months, peak in first 2-4 months) 2, 4
• Do not overlook cholestatic injury pattern – pazopanib can cause acute cholestatic hepatitis with severe jaundice, which may require steroid therapy if severe 4, 5
• Do not rechallenge without identifying alternative cause – if no other explanation is found, permanent discontinuation is required 1

Special Considerations

Pazopanib-induced liver injury can manifest as hepatocellular, cholestatic, or mixed patterns 4, 5. The isolated bilirubin elevation at week 6 with normal ALT suggests either:

• Early cholestatic injury (check alkaline phosphatase on repeat testing) 2
• Unconjugated hyperbilirubinemia from Gilbert's syndrome or hemolysis 1
• Progression of underlying liver disease from metastases 4

The presence of normal ALT does not provide reassurance – cholestatic DILI can present with bilirubin elevation preceding or occurring without significant transaminase elevation 2, 4.