Sunitinib-Induced Acute Liver Failure

Aqsa, Anum; Droubi, Sami; Amarnath, Shivantha; Almoussawi, Hassan; Abergel, Jeffrey

doi:10.1159/000511249

Cited by 10 publications

(10 citation statements)

References 8 publications

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“…Meta-analysis indicated safety and limited benefit regarding prolongation of patient survival with native liver without transplantation and survival after transplantation however, with no improvement of overall survival [ 70 ] NAC significantly reduces the level of reactive oxygen species produced by sunitinib and crizotinib and reduces sunitinib- and crizotinib-induced mitochondrial apoptosis and cellular damage. The use of NAC has been reported in several case reports of fulminant acute liver failure associated with TKIs [ 17 , 71 – 73 ].…”

Section: Discussionmentioning

confidence: 99%

“…Fulminant liver failure associated with sunitinib treatment is rare. Several cases of serious sunitinibinduced acute liver failure, including fatal cases, have been reported in the literature [17][18][19][20][21][22]. A meta-analysis of 3691 patients focusing on the incidence and relative risk of liver injury in patients treated with anti-angiogenic TKIs found that liver injury of sunitinib, pazopanib or other anti-angiogenic TKIs did not depend on the type of disease [23].…”

Section: Introductionmentioning

confidence: 99%

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Severe tyrosine-kinase inhibitor induced liver injury in metastatic renal cell carcinoma patients: two case reports assessed for causality using the updated RUCAM and review of the literature

et al. 2022

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Background Sunitinib and pazopanib are both oral small molecule multityrosine kinase inhibitors (MTKI) used in the treatment of renal cell carcinoma (RCC). Hepatotoxicity or “liver injury” is the most important adverse effect of pazopanib administration, but little is known about the underlying mechanism. Liver injury may also occur in patients treated with sunitinib, but severe toxicity is extremely rare. Herein we report two new cases of severe liver injury induced by MTKI. Both cases are unique and exceptional. We assessed both cases for drug-induced liver injury (DILI) using the updated score Roussel Uclaf causality assessment method (RUCAM). The literature on potential pathogenic mechanisms and precautionary measures is reviewed. Case presentation A case of a metastatic RCC (mRCC) patient treated with pazopanib who had manifestation of severe liver injury is presented. These manifestations consisted of grade 4 alanine aminotransferase (ALT) increase and grade 4 hyperbilirubinemia. Alternate causes of acute or chronic liver disease were excluded. The patient gradually recovered from the liver injury and refused any further therapy for mRCC. The patient was diagnosed with acute myeloid leukemia (AML) two years later and eventually succumbed to the disease. The second case describes a mRCC patient treated with sunitinib for 3,5 years and fatal liver failure after 2 weeks of clarithromycin co-medication for acute bronchitis. Conclusions Liver injury has been commonly observed in TKI-treated patients with unpredictable course. Management requires regular routine liver enzyme-monitoring and the collaboration of medical oncologist and hepatologist. There is an unmet medical need for a risk stratification and definition of predictive biomarkers to identify potential genetic polymorphisms or other factors associated with TKI-induced liver injury. Any potential unrecommended concomitant therapy has to be avoided.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Severe tyrosine-kinase inhibitor induced liver injury in metastatic renal cell carcinoma patients: two case reports assessed for causality using the updated RUCAM and review of the literature

et al. 2022

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“…As of October 2019, the FDA has approved 53 small molecule kinase inhibitors, seven (sunitinib, lapatinib, pazopanib, regorafenib, ponatinib, idelalisib, pexidartinib) of which had a black box warning of liver toxicity, and twenty-nine of which had warnings and precautions for hepatotoxicity in their product labeling (26). Many case reports demonstrated that crizotinib and sunitinib induced hepatotoxicity, even acute liver failure (ALF) (27)(28)(29). However, dose adjustment or drug discontinuation are the common strategies to reduce or manage hepatotoxicity induced by crizotinib or sunitinib.…”

Section: Discussionmentioning

confidence: 99%

An Insight on the Pathways Involved in Crizotinib and Sunitinib Induced Hepatotoxicity in HepG2 Cells and Animal Model

et al. 2022

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Both crizotinib and sunitinib, novel orally-active multikinase inhibitors, exhibit antitumor activity and extend the survival of patients with a malignant tumor. However, some patients may suffer liver injury that can further limit the clinical use of these drugs, however the mechanisms underlying hepatotoxicity are still to be elucidated. Thus, our study was designed to use HepG2 cells in vitro and the ICR mice model in vivo to investigate the mechanisms of hepatotoxicity induced by crizotinib and sunitinib. Male ICR mice were treated orally with crizotinib (70 mg/kg/day) or sunitinib (7.5 mg/kg/day) for four weeks. The results demonstrated that crizotinib and sunitinib caused cytotoxicity in HepG2 cells and chronic liver injury in mice, which were associated with oxidative stress, apoptosis and/or necrosis. Crizotinib- and sunitinib-induced oxidative stress was accompanied by increasing reactive oxygen species and malondialdehyde levels and decreasing the activity of superoxide dismutase and glutathione peroxidase. Notably, the activation of the Kelch-like ECH-associated protein-1/Nuclear factor erythroid-2 related factor 2 signaling pathway was involved in the process of oxidative stress, and partially protected against oxidative stress. Crizotinib and sunitinib induced apoptosis via the mitochondrial pathway, which was characterized by decreasing Bcl2/Bax ratio to dissipate the mitochondrial membrane potential, and increasing apoptotic markers levels. Moreover, the pan-caspase inhibitor Z-VAD-FMK improved the cell viability and alleviated liver damage, which further indicated the presence of apoptosis. Taken together, this study demonstrated that crizotinib- and sunitinib-caused oxidative stress and apoptosis finally impaired hepatic function, which was strongly supported by the histopathological lesions and markedly increased levels of serum alanine aminotransferase, alkaline phosphatase and lactate dehydrogenase.

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“…individual patients [33,34]. As most of TKIs are metabolized by hepatic cytochrome P450 enzyme system, clinicians should be aware of potential hepatotoxicity with TKIs in patients with liver dysfunction.…”

Section: Hepatotoxicitymentioning

confidence: 99%

“…In order to overcome the necessity for separation and washing steps of the filtration binding assay, the "mix and read" scintillation proximity assays were developed [49]. Reaction Biology Corporation's 33 PanQinase™ is an example of a scintillation proximity assay whereby the reaction with [ 33 P]-ATP is performed using microtiter plates coated with scintillant for detection [50]. A variety of radio isotypes can be utilized in a scintillation proximity assay [49].…”

Section: Scintillation Proximity Assaymentioning

confidence: 99%

Protein Kinase Inhibitors - Selectivity or Toxicity?

Grossman¹,

Adler²

2021

Biochemistry

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Protein kinases are attractive therapeutic targets for various indications including cancer, cardiovascular, neurodegenerative and autoimmune diseases. This is due to the fact that they play key roles in the regulation of cell cycle, metabolism, cell adhesion, angiogenesis, regeneration and degeneration. Protein kinase families share a common catalytic core and hence usually display clear sequence and structural similarity. These sequence and structural similarities can lead to a lack of selectivity and off-target toxicity of drug candidates. The lack of selectivity can be beneficial but can also cause adverse toxicities which result in the discontinuation of promising drug candidates. The chapter reviews the challenges and common toxicities of protein kinase inhibitors and the latest advances in in-vitro and in-silico assays to screen for selectivity. The various methods for quantifying selectivity of kinase inhibitors and future directions including emerging more selective and safer kinase inhibitors have also been discussed.

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Sunitinib-Induced Acute Liver Failure

Cited by 10 publications

References 8 publications

Severe tyrosine-kinase inhibitor induced liver injury in metastatic renal cell carcinoma patients: two case reports assessed for causality using the updated RUCAM and review of the literature

Severe tyrosine-kinase inhibitor induced liver injury in metastatic renal cell carcinoma patients: two case reports assessed for causality using the updated RUCAM and review of the literature

An Insight on the Pathways Involved in Crizotinib and Sunitinib Induced Hepatotoxicity in HepG2 Cells and Animal Model

Protein Kinase Inhibitors - Selectivity or Toxicity?

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