Pazopanib is a multi-kinase inhibitor active against vascular endothelial growth factor receptors-1, -2 and -3 that is used in the therapy of advanced renal cell carcinoma and soft tissue sarcomas. Pazopanib therapy is commonly associated with transient elevations in serum aminotransferase during therapy and has been linked to rare, but occasionally severe and even fatal cases of clinically apparent acute liver injury.
Pazopanib (paz oh’ pa nib) is an orally available, multi-kinase inhibitor, most potently inhibiting the tyrosine kinase receptors of vascular endothelial growth factor (VEGF) 1, 2 and 3 which are associated with tumor growth and angiogenesis. Pazopanib also has activity against c-KIT (an abnormal tyrosine kinase found in gastrointestinal stromal tumors) and the platelet derived growth factor (PDGF) receptor. Clinical trials of pazopanib in malignant diseases in humans have shown activity against renal cell carcinoma and soft tissue sarcoma and promising effects in ovarian and thyroid cancer. Pazopanib received approval for use in the United States in 2012 and current indications include advanced renal cell cancer and soft tissue sarcomas. Pazopanib is available in tablets of 200 and 400 mg under the brand name Votrient. The typical dose is 800 mg once daily. Lower doses are recommended for patients with moderate-to-severe liver disease (200 mg daily) and the dose can be reduced to 400 mg daily for toxicity. Common side effects include fatigue, diarrhea, hypertension, hair color changes, anorexia, nausea, and bone marrow suppression. Uncommon, but potentially severe side effects include prolonged QTc intervals, hemorrhages, arterial thrombosis and visceral perforations and fistulae.
In large clinical trials, abnormalities in routine liver tests were common in patients treated with pazopanib, with serum aminotransferase elevations occurring in up to half of patients and total serum bilirubin in approximately one-third. ALT and AST values greater than 5 times the upper limit of normal (ULN) occurred in 8% of patients and combinations of ALT and bilirubin elevations in 1% to 2%. In preliminary trials of pazopanib in various solid tumors, there were rare reports of hepatitis with jaundice in <1% of patients. Subsequently, fatal instances of liver injury have been reported and the clinical features of the hepatotoxicity have been better defined. The clinical onset is typically within 4 to 12 weeks of starting pazopanib and the pattern of serum enzyme elevations is usually mixed. Immunoallergic and autoimmune features are not present. The course is typically self-limited, but can be prolonged and severe and fatal instances have been reported (Case 1).
Mechanism of Injury
The mechanism of injury accounting for serum enzyme elevations during pazopanib therapy is not known. Retrospective analyses and genetic studies have suggested that other medications (simvastatin) and HFE polymorphisms may play a role in serum aminotransferase elevations and Gilbert syndrome in hyperbilirubinemia. Pazopanib is metabolized in the liver largely through the CYP 3A4 pathway and liver injury may be related to production of a toxic intermediate. Pazopanib is susceptible to drug-drug interactions with agents that inhibit or induce hepatic CYP 3A4 activity.
Outcome and Management
Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) or any elevations accompanied by jaundice or symptoms should lead to dose reduction or temporary cessation. There does not appear to be cross reactivity in risk for hepatic injury between pazopanib and other kinase inhibitors and, in some situations, switching to another tyrosine kinase receptor inhibitor may be appropriate.
Case 1. Severe acute liver injury and hepatic failure due to pazopanib.
[Modified from: Klempner SJ, Choueiri TK, Yee E, Doyle LA, Schuppan D, Atkins MB. Severe pazopanib-induced hepatotoxicity: clinical and histologic course in two patients. J Clin Oncol 2012; 30: e264-8. PubMed Citation]
A 77 year old man with metastatic renal cell carcinoma developed jaundice 6 weeks after starting pazopanib (800 mg daily). He had no previous history of liver disease and had normal routine liver tests before therapy and after 2 weeks of treatment (Table). He had no risk factors for viral hepatitis or history of alcohol abuse and was taking no other potentially hepatotoxic medications. On presentation, serum bilirubin was 6.3 mg/dL, ALT 759 U/L, AST 296 U/L and alkaline phosphatase 729 U/L. Pazopanib was stopped promptly and he was monitored closely. Tests for viral hepatitis A, B and C and cytomegalovirus infection were negative as were routine autoantibodies. A liver biopsy showed acute cholestatic hepatitis with mild bile duct injury. While serum aminotransferase levels rapidly fell to near normal levels, serum alkaline phosphatase remained high and bilirubin levels rose. Four weeks after presentation, the prothrombin time began to rise and the patient died of hepatic failure approximately 9 weeks after initial presentation.
|Medication:||Pazopanib (800 mg daily)|
|Pattern:|| Mixed (R~3: normal values not provided)|
|Severity:||5+ (hepatic failure and death)|
|Other medications:||None mentioned|
|Time After Starting
||Time After Stopping
|Alk P (U/L)
Elevations in serum aminotransferase levels occur in up to 50% of patients treated with pazopanib and rise to above 5 times ULN (approximately 200 U/L) in 8% of patients. Regular monitoring of liver tests is recommended. In this patient, monitoring of liver enzymes was done, but he presented with clinically apparent liver injury despite such monitoring and progressed to hepatic failure despite prompt discontinuation of therapy. The initial pattern of liver enzyme elevations was mixed, with prominent elevations in both serum aminotransferase and alkaline phosphatase levels. Subsequently, serum ALT levels fell, but alkaline phosphatase levels remained high and bilirubin levels continued to rise. A liver biopsy was done that reportedly showed active cholestatic hepatitis with some degree of bile duct injury and ductular proliferation. Within a few weeks, signs of hepatic failure arose and the patient died 9 weeks after presentation with what might be considered a subacute hepatic failure. The patient’s age and other comorbidities may have contributed to the poor outcome. A second patient (62 year old man) described in this report had a similar presentation with a mixed pattern of serum enzymes (ALT 935 U/L, Alk P 784 U/L) and jaundice (bilirubin 3.7 mg/dL), but had spontaneous improvement starting 3 weeks after stopping pazopanib and ultimate complete recovery.
REPRESENTATIVE TRADE NAMES
Pazopanib – Votrient®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NO.
References updated: 12 July 2014
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