Nilotinib-induced liver injury

Abstract

Introduction: Nilotinib is a selective inhibitor of the BCR-ABL tyrosine kinase receptor and is used in the management of chronic myelogenous leukemia (CML). Nilotinib therapy at high doses is associated with elevated serum bilirubin levels. If the serum bilirubin level exceeds 3 times the upper limit of normal, the recommendation is to either adjust nilotinib dosage or temporarily discontinue the treatment. However, it is unclear whether hyperbilirubinemia indicates obvious liver histology damage. Patient concerns: A 24-year-old man with confirmed CML was treated with nilotinib therapy and developed hyperbilirubinemia after the treatment. Although the first remission of the hyperbilirubinemia was achieved after dose adjustment, the hematological parameters deteriorated. Thus, we initiated an antineoplastic therapy (at the standard dose) until complete remission of the CML was achieved. The pathogenic mechanism of hyperbilirubinemia may be related to the inhibition of uridine diphosphate-glucuronosyltransferase (UGT1A1) activity. Liver histological analysis revealed no significant liver damage. In addition, the patient had no family history of hyperbilirubinemia and liver disease. Diagnosis: The patient was admitted to our hospital under the diagnosis of hyperbilirubinemia, and histopathology by liver biopsy showed no obvious damage. We also detected a UGT1A1 mutation [ex1 c.686C > A (p.Pro229Gln)] in the patient and his mother. Interventions: When the nilotinib dose was decreased to 300 mg daily, the total bilirubin (TBIL) level decreased to 30 to 50 μmol/L for 1 month. However, because the Bcr-Abl/Abl IS ratio did not correspond to the major molecular response (MMR; <0.1%), the nilotinib dose was readjusted to 400 mg daily. One week later, the TBIL and indirect bilirubin levels increased to 89 and 79 μmol/L, respectively. The levels of alanine transaminase and other liver functional indicators were normal. Outcomes: A Naranjo Adverse Drug Reaction (ADR) Probability Scale score of 13 indicates that hyperbilirubinemia is attributed to ADR caused by nilotinib rather than by drug-induced liver injury. Conclusion: Although reducing the nilotinib dose can alleviate the occurrence of hyperbilirubinemia, the effect of MMR is also reduced. Treatment of CML without dose adjustment or discontinuation of nilotinib therapy may be more advantageous.

Predictive Model for Drug-Induced Liver Injury Using Deep Neural Networks Based on Substructure Space

“…These results implied that our model had a good predictive performance to accurately identify DILI drugs. [27] 5,493,444 7.0% DILI-positive 0.999 Rilpivirine [28] 6,451,164 5.0% DILI-positive 0.994 Escitalopram [29] 146,570 5.0% DILI-positive 0.989 Nilotinib [30] 644,241 7.6% DILI-positive 0.982 Olmesartan [31] 158,781 6.3% DILI-positive 0.974 Mesterolone [32] 15,020 4.1% DILI-positive 0.971 Levothyroxine [33] 5819 3.9% DILI-positive 0.965 Zanubrutinib [34] 135,565,884 6.4% DILI-positive 0.922 Phenprobamate [35] 4770 2.8% DILI-positive 0.896 Apixaban [36] 10,182,969 5.5% DILI-positive 0.804 Fasiglifam [37] 24,857,286 7.0% DILI-positive 0.660 Pirfenidone [38] 40,632 2.6% DILI-positive 0.608 Ligandrol [39] 44,137,686 4.6% DILI-negative 0.378 Ulipristal acetate [40] 130,904 6.5% DILI-negative 0.036 DILI, drug-induced liver injury.…”

Pexidartinib Triggers the Risk of Drug-drug Interactions by Inhibiting UDP-glucuronosyltransferase in vitro

“…Inhibition of UGTs activities by xenobiotics may increase risk of drug adverse reactions, as well as cause metabolic disorders of endogenous compounds. Previous studies have indicated many TKIs including sorafenib, regorafenib, nilotinib, lapatinib, erlotinib, and pazopanib exhibit strong inhibitory effects on UGT1A1, which is closely associated with the development of hyperbilirubinemia in patients [15][16][17][18]. Clinical studies have confirmed that patients treated with pexidartinib are more likely arise hyperbilirubinemia in clinic [19].…”