Genetic variation in UGT1A1 typical of Gilbert syndrome is associated with unconjugated hyperbilirubinemia in patients receiving tocilizumab
| Autor: | Robert Pilson, Andrew Hemmings, J Wang, Soren Germer, Joel Krasnow, Ryma Benayed, Neil Kaplowitz, Mitchell Martin, Olivia Spleiss, Janet S. Lee, Adam Platt, Michael E. Weinblatt, Andrew Kenwright |
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| Rok vydání: | 2011 |
| Předmět: |
Gilbert Syndrome
medicine.medical_specialty Genotype Arthritis Antibodies Monoclonal Humanized Polymorphism Single Nucleotide Gastroenterology Arthritis Rheumatoid chemistry.chemical_compound Tocilizumab Immunopathology Internal medicine Genetics medicine Humans Glucuronosyltransferase General Pharmacology Toxicology and Pharmaceutics Molecular Biology Genetic Association Studies Genetics (clinical) Hyperbilirubinemia Unconjugated hyperbilirubinemia business.industry Homozygote Antibodies Monoclonal Bilirubin medicine.disease Clinical Trials Phase III as Topic chemistry Rheumatoid arthritis Mutation Immunology Monoclonal Molecular Medicine Gilbert Disease business Pharmacogenetics |
| Zdroj: | Pharmacogenetics and Genomics. 21:365-374 |
| ISSN: | 1744-6872 |
| DOI: | 10.1097/fpc.0b013e32834592fe |
| Popis: | Tocilizumab, a monoclonal antibody to interleukin-6 receptor, was recently approved for the treatment of moderate-to-severe rheumatoid arthritis. Two patients during clinical development met laboratory, but not clinical, criteria for Hy's law with bilirubin elevations suspected as a result of genetic variation in uridine diphosphoglucose glucuronosyltransferase (UGT1A1) typical of Gilbert syndrome.Genotyping of the two cases potentially meeting with Hy's law was performed using commercially available procedures. UGT1A1 single nucleotide polymorphism data were extracted from a genome-wide array database for 1187 patients from tocilizumab trials, and associations of UGT1A1 genotypes with bilirubin elevations were analyzed using logistic regression for associations with baseline and change from baseline in bilirubin levels as continuous variables.Bilirubin elevations were not associated with clinical adverse events. Both patients potentially meeting Hy's law carry homozygous UGT1A1*28 alleles and UGT1A1*60 alleles. UGT1A1*28 and three additional single nucleotide polymorphisms showed odds ratios greater than 25 for associations with elevated bilirubin. The presence of rs6742078 accounted for 32% of the total variance in bilirubin (P=2.2×10).Bilirubin increases occurring with tocilizumab appear to be related to anti-inflammatory effects extending to the liver. Thus, in the absence of other signs of hepatic dysfunction, bilirubin elevations after treatment with tocilizumab have a high probability of association with UGT1A1 polymorphism, which should alleviate concerns of serious hepatotoxicity. Our results underscore the value of genotyping in the clinical trial setting to avoid misinterpretations that could lead to terminating development of a promising new agent. |
| Databáze: | OpenAIRE |
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