Pazopanib-induced hyperbilirubinemia is associated with Gilbert's syndrome UGT1A1 polymorphism

Background: Pazopanib has shown clinical activity against multiple tumour types and is generally well tolerated. However, isolated elevations in transaminases and bilirubin have been observed. This study examined polymorphisms in molecules involved in pharmacokinetic and pharmacodynamic pathways of...

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Bibliographic Details
Published in:British journal of cancer 2010-04, Vol.102 (9), p.1371-1377
Main Authors: Xu, C-F, Reck, B H, Xue, Z, Huang, L, Baker, K L, Chen, M, Chen, E P, Ellens, H E, Mooser, V E, Cardon, L R, Spraggs, C F, Pandite, L
Format: Article
Language:English
Subjects:
631/208/726/649
631/92/436/1729
692/699/317
692/699/67/589/1588/1351
Aged
Alanine Transaminase - metabolism
Antineoplastic Agents - adverse effects
Antineoplastic Agents - therapeutic use
Bilirubin - metabolism
Biomedical and Life Sciences
Biomedicine
Cancer Research
Carcinoma, Renal Cell - drug therapy
Carcinoma, Renal Cell - surgery
Clinical Trials, Phase II as Topic
Clinical Trials, Phase III as Topic
Drug Resistance
Enzymes
Epidemiology
FDA approval
Female
Genetic research
Genotype
Gilbert Disease - genetics
Glucuronosyltransferase - antagonists & inhibitors
Glucuronosyltransferase - genetics
Growth factors
Humans
Hyperbilirubinemia - chemically induced
Hyperbilirubinemia - epidemiology
Hyperbilirubinemia - etiology
Informed consent
Kidney cancer
Kidney Neoplasms - drug therapy
Kidney Neoplasms - surgery
Kinases
Liver
Liver - enzymology
Male
Medical research
Metabolism
Middle Aged
Molecular Diagnostics
Molecular Medicine
Nephrectomy
Oncology
Polymorphism
Polymorphism, Genetic
Pyrimidines - adverse effects
Pyrimidines - therapeutic use
R&D
Research & development
Self report
Sulfonamides - adverse effects
Sulfonamides - therapeutic use
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Summary:Background: Pazopanib has shown clinical activity against multiple tumour types and is generally well tolerated. However, isolated elevations in transaminases and bilirubin have been observed. This study examined polymorphisms in molecules involved in pharmacokinetic and pharmacodynamic pathways of pazopanib and their association with hepatic dysfunction. Methods: Twenty-eight polymorphisms in 11 genes were evaluated in pazopanib-treated renal cell carcinoma patients. An exploratory analysis was conducted in 116 patients from a phase II study; a replication study was conducted in 130 patients from a phase III study. Results: No polymorphisms were associated with alanine aminotransferase elevation. The Gilbert's uridine-diphosphoglucuronate glucuronosyltransferase 1A1 ( UGT1A1 ) TA-repeat polymorphism was significantly associated with pazopanib-induced hyperbilirubinemia in the phase II study. This association was replicated in the phase III study ( P
ISSN:0007-0920
1532-1827
DOI:10.1038/sj.bjc.6605653