title: Genetic variation in UGT1A1 typical of Gilbert syndrome is associated with unconjugated hyperbilirubinemia in patients receiving tocilizumab.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Roche, Nutley, New Jersey. janet_s.lee@roche.com
authors.forename: Janet S
authors.initials: JS
authors.lastname: Lee
authors.forename: Jianmei
authors.initials: J
authors.lastname: Wang
authors.forename: Mitchell
authors.initials: M
authors.lastname: Martin
authors.forename: Soren
authors.initials: S
authors.lastname: Germer
authors.forename: Andrew
authors.initials: A
authors.lastname: Kenwright
authors.forename: Ryma
authors.initials: R
authors.lastname: Benayed
authors.forename: Olivia
authors.initials: O
authors.lastname: Spleiss
authors.forename: Adam
authors.initials: A
authors.lastname: Platt
authors.forename: Robert
authors.initials: R
authors.lastname: Pilson
authors.forename: Andrew
authors.initials: A
authors.lastname: Hemmings
authors.forename: Michael E
authors.initials: ME
authors.lastname: Weinblatt
authors.forename: Neil
authors.initials: N
authors.lastname: Kaplowitz
authors.forename: Joel
authors.initials: J
authors.lastname: Krasnow
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D001663:Bilirubin / Q000097:blood*; D017326:Clinical Trials, Phase III as Topic; D056726:Genetic Association Studies; D005838:Genotype; D005878:Gilbert Disease / Q000235:genetics*; D014453:Glucuronosyltransferase / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D006932:Hyperbilirubinemia / Q000209:etiology* / Q000235:genetics*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D000099148:UGT1A1 Enzyme
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001663:Bilirubin; D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme; C502936:tocilizumab