Multi-Targeted Tyrosine Kinase Inhibitor-Induced Hyperammonemic Encephalopathy: a Report of Two Cases Using Pazopanib, Sunitinib, and Regorafenib

Kongsuphon, Noppadon; Soukavanitch, Maturos; Teeraaumpornpunt, Noramon; Konmun, Jitprapa; Ativitavas, Touch; Ngamphaiboon, Nuttapong

doi:10.1007/s12029-018-0067-6

Cited by 5 publications

(5 citation statements)

References 10 publications

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“…22 Other report, have hypothesized that the anti-angiogenetic effect of the MTKI could alter vascular permeability on blood-brain barrier leading to an accumulation of ammonia in the central nervous system than usual. 13 Apart from vascular causes, that were ruled out, we hypothesized that a biochemical mechanism could be responsible of this fatal adverse event since the clinical manifestations are similar than those presented in patients with urea cycle disorders. We made a literature review of the possible relationship between the urea cycle and the molecular inhibition exerted by MTKI.…”

Section: Discussionmentioning

confidence: 99%

“…11 Other rarer adverse events have been reported in clinical trials including hepatotoxicity or PRES. 12 However, there are important adverse events associated with MTKI not reported in clinical studies but are described in the literature like hyperammonemic encephalopathy induced by regorafenib 1314–15 and other MTKI 1617–18 (Table 1). Trametinib is a Mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor indicated in BRAFV600 mutated melanoma and non-small cell lung cancer in combination with the B-RafV600E inhibitor dabrafenib.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Hyperammonemic encephalopathy after tyrosine kinase inhibitors: A literature review and a case example

García-Díaz,

Eremiev,

Gómez-Alonso

et al. 2024

J Oncol Pharm Pract

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Objective To review the evidence of uncommon but fatal adverse event of hyperammonemic encephalopathy by tyrosine kinase inhibitors (TKI) and the possible mechanisms underlying this condition and to describe the case of a patient that developed drug-induced hyperammonemic encephalopathy related to TKI. Data Sources Literature search of different databases was performed for studies published from 1 January 1992 to 7 May 2023. The search terms utilized were hyperammonemic encephalopathy, TKI, apatinib, pazopanib, sunitinib, imatinib, sorafenib, regorafenib, trametinib, urea cycle regulation, sorafenib, carbamoyl-phosphate synthetase 1, ornithine transcarbamylase, argininosuccinate synthetase, argininosuccinate lyase, arginase 1, Mitogen activated protein kinases (MAPK) pathway and mTOR pathway, were used individually search or combined. Data Summary Thirty-seven articles were included. The articles primarily focused in hyperammonemic encephalopathy case reports, management of hyperammonemic encephalopathy, urea cycle regulation, autophagy, mTOR and MAPK pathways, and TKI. Conclusion Eighteen cases of hyperammonemic encephalopathy were reported in the literature from various multitargeted TKI. The mechanism of this event is not well-understood but some authors have hypothesized vascular causes since some of TKI are antiangiogenic, however our literature review shows a possible relationship between the urea cycle and the molecular inhibition exerted by TKI. More preclinical evidence is required to unveil the biochemical mechanisms responsible involved in this process and clinical studies are necessary to shed light on the prevalence, risk factors, management and prevention of this adverse event. It is important to monitor neurological symptoms and to measure ammonia levels when manifestations are detected.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Hyperammonemic encephalopathy after tyrosine kinase inhibitors: A literature review and a case example

García-Díaz,

Eremiev,

Gómez-Alonso

et al. 2024

J Oncol Pharm Pract

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“…Case reports have described hyperammonemia in a narrow spectrum of tumor types (e.g. GIST, myeloma, neuroendocrine tumors, hepatocellular carcinoma, renal cell carcinoma, and colorectal carcinoma) [3][4][5][6][7][8][9][10][11][12][13][14]. GIST in particular is well known for complications related to endophytic growth leading to GI bleeding, obstruction, and perforation.…”

Section: Discussionmentioning

confidence: 99%

“…The underlying mechanism of TKI-induced hyperammonemic encephalopathy is poorly understood but has been well-documented across multiple therapeutic agents. Sunitinib, regorafenib, pazopanib, and sorafenib specifically have been linked with hyperammonemic encephalopathy across the aforementioned tumor types in patients with and without chronic liver disease [ 4 ]. Proposed mechanisms invoke the principle of TKI-mediated derangement of VEGF and platelet-derived growth factor receptor signaling resulting in damage to the cerebral vascular endothelium.…”

Section: Discussionmentioning

confidence: 99%

A Case of Non-cirrhotic Hyperammonemic Encephalopathy in a Patient With Metastatic Gastrointestinal Stromal Tumor

Jeong¹,

Abiri²,

Cai³

et al. 2023

Cureus

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Acute toxic encephalopathy (ATE) is a widely recognized medical emergency with an expansive differential. One particular known etiology for ATE is elevated ammonia, a powerful neurotoxin that often presents with clinical findings of confusion, disorientation, tremors, and in severe cases, coma and death. Hyperammonemia is most commonly associated with liver disease and presents as hepatic encephalopathy in the setting of decompensated cirrhosis; however, in rare cases, a patient may suffer from non-cirrhotic hyperammonemic encephalopathy. We describe the case of a 61-year-old male with metastatic gastrointestinal stromal tumor who was diagnosed with non-cirrhotic hyperammonemic encephalopathy, and briefly explore the literature describing its mechanisms.

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Pazopanib/regorafenib/sunitinib

2019

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Multi-Targeted Tyrosine Kinase Inhibitor-Induced Hyperammonemic Encephalopathy: a Report of Two Cases Using Pazopanib, Sunitinib, and Regorafenib

Cited by 5 publications

References 10 publications

Hyperammonemic encephalopathy after tyrosine kinase inhibitors: A literature review and a case example

Hyperammonemic encephalopathy after tyrosine kinase inhibitors: A literature review and a case example

A Case of Non-cirrhotic Hyperammonemic Encephalopathy in a Patient With Metastatic Gastrointestinal Stromal Tumor

Pazopanib/regorafenib/sunitinib

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