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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Sunitinib

Last Update: June 27, 2018.

OVERVIEW

Introduction

Sunitinib is multi-specific tyrosine kinase receptor inhibitor that is used in the therapy of gastrointestinal stromal tumors and advanced renal cell carcinoma. Sunitinib therapy is associated with transient elevations in serum aminotransferase and bilirubin levels and rare instances of clinically apparent acute liver injury.

Background

Sunitinib (soo ni' ti nib) is an inhibitor of several tyrosine kinase receptors which are associated with tumor growth and angiogenesis. The tyrosine kinase receptors of cancer cells are often mutated and can cause unregulated cell growth and proliferation. Sunitinib is one of several tyrosine kinase receptor inhibitors that have been introduced into cancer chemotherapy and are specially directed at molecular abnormalities that occur in cancer cells. Inhibition of the receptor can lead to dramatic reversal of progression the cancer, although sometimes limited by the development of tumor resistance caused by mutations in the kinase. Sunitinib has special activity against the abnormal tyrosine kinase (cKit) that is found in gastrointestinal stromal tumors (GIST). Sunitinib also has activity against the receptors for platelet derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Sunitinib received approval for use in the United States in 2006. Current indications are for unresectable or metastatic GIST with positive cKit (CD117), advanced renal cell carcinoma and advanced pancreatic neuroendocrine tumors. Sunitinib is also used in patients who are intolerant or become resistant to imatinib, the initial tyrosine kinase receptor inhibitor that has special activity against chronic myelogenous leukemia (CML) bearing the Philadelphia chromosome. Sunitinib is available in capsules of 12.5, 25 and 50 mg under the brand name Sutent. The typical dose of sunitinib is in cycles of 4 weeks, followed by a rest period of 2 weeks, using a starting dose of 37.5 or 50 mg daily and increasing or decreasing in 12.5 mg increments, with each cycle based upon tolerance and response. Side effects include fatigue, diarrhea, anorexia, skin discoloration, rash, hand-foot syndrome, edema, muscle cramps, arthralgias, headache, abdominal discomfort, anemia, cough, and pruritus. Uncommon side effects include heart failure, pancreatitis and renal failure.

Hepatotoxicity

In large clinical trials of sunitinib, elevations in serum aminotransferase levels were common, occurring in 39% of sunitinib vs 23% of placebo recipients. Values greater than 5 times the upper limit of normal (ULN) occurred in only 2% to 3% of sunitinib recipients (and 1% of controls). These abnormalities were usually asymptomatic. Dose adjustment or temporary discontinuation and restarting at a lower dose is recommended if enzyme levels are markedly elevated (ALT or AST persistently greater than 5 times ULN or bilirubin more than 3 times ULN). Sunitinib therapy is also associated with a high rate of serum bilirubin elevations, generally in the mild-to-moderate range and not in association with ALT or AST elevations. These changes are probably due to interaction with hepatic UDP-glucuronyltransferase, the enzyme that is also responsible for bilirubin excretion.

More importantly, there have been several case reports of clinically apparent liver injury attributed to sunitinib therapy. The time to onset was after several cycles of therapy. The pattern of serum enzyme elevations was typically hepatocellular and the clinical presentation resembled acute hepatic necrosis. In some instances, the injury may have been due to hypotension, shock or ischemia rather than direct hepatotoxicity (Case 1). Regardless, the injury can be severe and several instances of acute liver failure and death have been reported. Immunoallergic features (rash, fever and eosinophilia) are not common.

Finally, sunitinib has also been reported to cause hyperammonemia and encephalopathy in rare patients with cancer treated with conventional or even low oral doses (Case 2). The time to onset was within 1 to 3 weeks, presenting with confusion and irritability with minimal elevations in serum enzymes and bilirubin and marked increases (4-10 times the ULN) in serum ammonia. Recovery is rapid once sunitinib is stopped and the syndrome can recur with re-exposure. Interesting, there appears to be little cross-reactivity to this complication with other tyrosine kinase inhibitors.

Likelihood score: B (highly likely cause of clinically apparent liver injury, including hyperammonemic syndrome).

Mechanism of Injury

The clinical features of cases of severe acute liver injury due to sunitinib have suggested ischemic damage that may be related to hypotension and anoxia, rather than direct hepatic injury. Sunitinib is metabolized in the liver largely through the CYP 3A4 pathway and liver injury may be related to production of a toxic intermediate. The cause of hyperammonemia due to sunitinib is unknown, but it appears to be idiosyncratic and may relate to inhibition of urea cycle enzymes by sunitinib.

Outcome and Management

Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) should lead to dose reduction or temporary cessation. In some situations, therapy can be restarted particularly with concurrent prednisone (10-20 mg daily). In patients with clinically apparent liver injury and jaundice, restarting therapy should be done with caution. There does not appear to be cross reactivity in risk for hepatic injury between sunitinib and other tyrosine kinase inhibitors and, in some situations, switching to another tyrosine kinase receptor inhibitor may be appropriate. Cases of acute liver failure have occurred in patients receiving sunitinib. In using this medication, other potentially hepatotoxic agents should be avoided.

Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors

CASE REPORTS

Case 1. Severe acute liver injury during sunitinib therapy.

[Modified from: Mueller EW, Rockey ML, Rashkin MC. Sunitinib-related fulminant hepatic failure: case report and review of the literature. Pharmacotherapy 2008; 28: 1066-70. PubMed Citation]

A 75 year old woman with metastatic renal cell carcinoma developed severe diarrhea and dehydration after a fifth 4-week cycle of sunitinib and was found to be jaundiced. Her renal carcinoma had been diagnosed six months earlier, at which time she had undergone right nephrectomy. Metastases were identified in the inferior vena cava and lungs and she was started on sunitinib in 4 week courses, followed by a rest period of 2 weeks. She had multiple side effects with chemotherapy including fatigue, arthralgias, dry mouth, thrombocytopenia, neutropenia, abdominal pain and diarrhea. Her liver tests were known to be normal before and during the first five cycles of sunitinib therapy (Table). Four days after the fifth cycle, she was brought to the hospital by her family because of dehydration and mental confusion following a 3 day history of diarrhea. She had no known liver disease, alcohol use or risk factors for viral hepatitis. Her past medical history included breast cancer treated with lumpectomy 7 years earlier as well as hypothyroidism, hypertension, chronic heart failure, gastroesophageal reflux disease, bladder surgery and carpal tunnel syndrome. Her other medications included letrozole, alendronate, irbesartan, docusate sodium, prochlorperazine, clonidine, lansoprazole, filgrastim and levothyroxine. On admission, she was tachypneic, but other vital signs were normal. Liver tests showed elevations in serum bilirubin (5.9 mg/dL) with marked elevations in serum aminotransferase levels (ALT 3332 U/L, AST 3872 U/L) and creatine kinase (21,729 U/L), with prolongation of the prothrombin time (INR 4.8) and elevation in serum ammonia (897 μg/dL). Serum blood urea nitrogen and creatinine were also elevated (84 and 2.7 mg/dL). Tests for hepatitis A, B and C were negative. Abdominal ultrasound showed no evidence of biliary obstruction. She was treated for suspected acute liver failure. With conservative medical management she began to improve, her mental status returning to normal within a few days and serum aminotransferase levels falling rapidly (Table). She was discharged after 7 days in the hospital and had normal liver tests when tested 1 month later.

Key Points

Medication:Sunitinib (50 mg daily in 5 4-week cycles)
Pattern:Hepatocellular (R=unable to calculate, no alkaline phosphatase results)
Severity:4+ (jaundice, hospitalization and features of hepatic failure)
Latency:~9 months
Recovery:1 month
Other medications:Stable doses of letrozole, alendronate, irbesartan, docusate sodium, prochlorperazine, clonidine, lansoprazole, filgrastim and levothyroxine

Laboratory Values

Time After StartingTime After StoppingALT (U/L)CPK (U/L)Bilirubin (mg/dL)Other
PrePre31-360.4-0.7Values before and during five cycles
Admitted for severe diarrhea and dehydration
9 months4 days333221,7295.9INR 4.8, Ammonia 897 μg/dL
5 days253499816.4
6 days223458246.4
7 days16327.0INR 1.7, Ammonia 85 μg/dL
8 days10606565.9
9 days6183294.6
10 days4651984.6INR 1.4
10 months1 month210.6
15 months6 months330.5
Normal Values <40 <250 <1.2

Comment

While the patient was considered to have acute liver failure due to sunitinib induced liver injury, a more likely cause was acute ischemia or shock causing centrolobular acute hepatic necrosis and attendant liver failure, coagulopathy and confusion. The clinical phenotype of the presentation and course was that of acute hepatic necrosis, with rapid rise and rapid fall in serum aminotransferase levels, accompanied with increase in creatine kinase and early appearance of coagulopathy, encephalopathy and renal dysfunction. Acute liver failure due to medications typically has a more insidious onset with hepatic failure arising in the setting of deep jaundice and recovery being slow and protracted. While sunitinib therapy is associated with a high rate of minor serum aminotransferase elevations (in up to 61%), these abnormalities are rarely severe (~2%), and are usually asymptomatic and rapidly resolve either spontaneously or with dose adjustment.

Case 2. Hyperammonemia and coma during sunitinib therapy.

[Modified from case 2 in: Lee NR, Yhim HY, Yim CY, Kwak JY, Song EK. Sunitinib-induced hyperammonemic encephalopathy in gastrointestinal stromal tumors. Ann Pharmacother 2011; 45: e56. PubMed Citation]

A 68 year old woman with metastatic gastrointestinal stomal tumors (GIST) of the cecum developed confusion and irritability 10 days after starting sunitinib (50 mg daily) and required emergency hospitalization. She had been treated with imatinib for 3 years, but had developed disease progression despite dose increases. She had no history of liver disease or risk factors for viral hepatitis and denied taking other medications except for lansoprazole (30 mg daily) and tramadol (40 mg daily). Laboratory tests showed minimal elevations in serum ALT (53 U/L) and AST (44 U/L) with normal serum bilirubin (0.7 mg/dL), but marked elevations in serum ammonia (Table). CT scans of the brain showed no abnormalities. Sunitinib was stopped and she was treated with hypdration and lactulose. She improved rapidly with ammonia levels decreasing within 24 hours and she was discharged four days later. However, she presented with a similar severe episode of confusion within a week, having restarted sunitinib immediately after discharge. Again she improved within 24 hours of stopping sunitinib for the second time and was discharged 4 days later. She did not restart sunitinib and had no further episodes of hyperammonemia.

Key Points

Medication: Sunitinib (50 mg daily of 10 days)
Pattern: Minimal enzyme elevations
Severity: 4+ (encephalopathy)
Latency: 10 days initially, 7 days on re-exposure
Recovery: 4 days
Other medications: Lansoprazole and tramadol

Laboratory Values

Time After StartingTime After StoppingAmmonia (μg/dL)Bilirubin (mg/dL)Other
PrePre0.4No known liver disease
0Sunitinib (50 mg daily) started for metastatic GIST
10 days03891.7Admission for confusion
11 days11161.7Clinically improved
14 days4 daysDischarged and sunitinib restarted
21 (7) days11 (0) days2101.5Re-admitted for confusion
(8) days(1) day591.5
(11) days(4) daysDischarged
Normal Values <45 <1.2

*Values parenthesis represent days after restarting or restopping sunitinib.

Comment

Hyperammonemic coma is a rare but distinctive syndrome that has been linked to therapy with valproic acid and with various cancer chemotherapeutic regimens. Patients are typically dehydrated and present with irritability, stupor and confusion progressing to frank coma. Routine liver tests are usually normal or minimally abnormal, but ammonia levels are high. The syndrome reverses rapidly once the causative medication is stopped, but it can be severe and fatalities have been reported. The cause of the syndrome is not known, but probably relates to inhibition of mitochondrial or urea cycle enzyme function rather than frank hepatic failure.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Sunitinib – Sutent®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Sunitinib 557795-19-4 C22-H27-F-N4-O2
Sunitinib Chemical Structure

ANNOTATED BIBLIOGRAPHY

References updated: 27 June 2018

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