Severe Drug-Induced Liver Injury from Combination Encorafenib/Binimetinib

Gravbrot, Nicholas; Sundararajan, Srinath

doi:10.1155/2019/3051945

Cited by 5 publications

(2 citation statements)

References 20 publications

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“…MEK inhibitors did not potently inhibit BSEP (Table 1) but showed clinical adverse effects of liver toxicity (Welsh and Corrie, 2015). The severity of liver injury increases when two inhibitors targeting the RAS/RAF/EMK/ERK pathway are combined (Gravbrot and Sundararajan, 2019). These results suggested that CYP7A1 induction could be a culprit for hepatotoxicity, independent of BSEP inhibition, and potentially explain the clinical observations for this class of drugs (Verzijl et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

CYP7A1 Gene Induction via SHP-Dependent or Independent Mechanisms can Increase the Risk of Drug-Induced Liver Injury Independently or in Synergy with BSEP Inhibition

Niu,

Xie,

Liu

et al. 2024

Drug Metab Dispos

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Drug-induced liver injury (DILI) is a frequent cause of clinical trial failures during drug development. While inhibiting BSEP is a well-documented DILI mechanism, interference with genes related to bile acid (BA) metabolism and transport can further complicate DILI development. Here, the effects of twenty-eight compounds on genes associated with BA metabolism and transport were evaluated, including those with discontinued development or use, boxed warnings, and clean labels for DILI. The study also included rifampicin and omeprazole, PXR and AhR ligands, and four mitogen-activated protein kinase kinase (MEK1/2) inhibitors. BSEP inhibitors with more severe DILI, notably pazopanib and CP-724714, significantly upregulated the expression of 7 alpha-hydroxylase (CYP7A1), independent of small heterodimer partner (SHP) expression. CYP7A1 expression was marginally induced by omeprazole. In contrast, its expression was suppressed by mometasone (10-fold), vinblastine (18-fold), hexachlorophene (2-fold), bosentan (2.1-fold), and rifampin (2-fold). All four MEK1/2 inhibitors that show clinical DILI were not potent BSEP inhibitors but significantly induced CYP7A1 expression, accompanied by a significant SHP gene suppression. SULT2A1 and BSEP were marginally upregulated, but no other genes were altered by the drugs tested. Protein levels of CYP7A1 were increased with the treatment of CYP7A1 inducers and decreased with obeticholic acid, an FXR ligand. CYP7A1 inducers significantly increased BA production in hepatocytes, indicating the overall regulatory effects of BA metabolism. This study demonstrates that CYP7A1 induction via various mechanisms can pose a risk for DILI, independently or in synergy with BSEP inhibition, and it should be evaluated early in drug discovery.

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Section: Discussionmentioning

confidence: 99%

CYP7A1 Gene Induction via SHP-Dependent or Independent Mechanisms can Increase the Risk of Drug-Induced Liver Injury Independently or in Synergy with BSEP Inhibition

Niu,

Xie,

Liu

et al. 2024

Drug Metab Dispos

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“…Binimetinib is a selective and orally available MEK1/2 inhibitor . Binimetinib in combination with encorafenib was developed for treating adult patients with unresectable or metastatic melanoma. , A recent report indicated that combination of encorafenib and binimetinib caused rare but severe liver injury . However, the mechanistic basis of the liver injury is unclear.…”

Section: Introductionmentioning

confidence: 99%

Binimetinib Is a Potent Reversible and Time-Dependent Inhibitor of Cytochrome P450 1A2

Dong

Liu

2021

Chem. Res. Toxicol.

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Binimetinib is a selective MEK1/2 inhibitor, which is indicative of melanoma. We aimed to investigate the inhibitory effect of binimetinib on cytochrome P450 using human liver microsomes. Binimetinib was demonstrated to display reversible and time-dependent inhibitory effects on human CYP1A2. Binimetinib can inhibit the activity of phenacetin deethylation with IC 50 of 5.6 μM. A 30 min preincubation of binimetinib with NADPH-supplemented human liver microsomes raised a significant left IC 50 shift (6.5-fold), from 5.69−0.88 μM. The inactivation parameters K inact and K I were 0.063 min −1 and 15.47 μM, and the half-life of inactivation was 11 min. Glutathione (GSH) and catalase/superoxide exhibited minor or no protective effect on binimetinib-induced enzyme inactivation. Trapping experiment by GSH induced a detection of GSH adduct, of which the formation was believed to be through the oxidation of electron-rich 1,4benzenediamine to reactive 1,4-diiminoquinone species. Cytochrome P450 3A4, 2C9, and 2D6 were involved in the bioactivation of binimetinib. In conclusion, binimetinib was proven to display reversible and time-dependent inhibitory effect on CYP1A2, which may have implications for the toxicity of binimetinib.

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Multiple drugs

2020

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Severe Drug-Induced Liver Injury from Combination Encorafenib/Binimetinib

Cited by 5 publications

References 20 publications

CYP7A1 Gene Induction via SHP-Dependent or Independent Mechanisms can Increase the Risk of Drug-Induced Liver Injury Independently or in Synergy with BSEP Inhibition

CYP7A1 Gene Induction via SHP-Dependent or Independent Mechanisms can Increase the Risk of Drug-Induced Liver Injury Independently or in Synergy with BSEP Inhibition

Binimetinib Is a Potent Reversible and Time-Dependent Inhibitor of Cytochrome P450 1A2

Multiple drugs

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