Genetic variation in XXXX typical of @entity9528 is associated with unconjugated hyperbilirubinemia in @entity1 receiving tocilizumab.

@entity1 @entity6912 @entity648 @entity31537 @entity409 @entity10497 @entity73027 @entity9528 @entity309
OBJECTIVE: Tocilizumab, a monoclonal antibody to @entity10497 , was recently approved for the treatment of moderate-to-severe @entity309 . Two @entity1 during clinical development met laboratory, but not clinical, criteria for Hy's law with @entity648 elevations suspected as a result of genetic variation in @entity31537 glucuronosyltransferase ( @entity6912 ) typical of @entity9528 . METHODS: Genotyping of the two cases potentially meeting with Hy's law was performed using commercially available procedures. @entity6912 single nucleotide polymorphism data were extracted from a genome-wide array database for 1187 @entity1 from tocilizumab trials, and associations of @entity6912 genotypes with @entity648 elevations were analyzed using logistic regression for associations with baseline and change from baseline in @entity648 levels as continuous variables. RESULTS: @entity648 elevations were not associated with clinical adverse events. Both @entity1 potentially meeting Hy's law carry homozygous @entity6912 *28 alleles and @entity6912 *60 alleles. @entity6912 *28 and three additional single nucleotide polymorphisms showed odds ratios greater than 25 for associations with elevated @entity648 . The presence of @entity73027 accounted for 32% of the total variance in @entity648 (P=2.2 10). CONCLUSION: @entity648 increases occurring with tocilizumab appear to be related to anti-inflammatory effects extending to the liver. Thus, in the absence of other signs of @entity409 , @entity648 elevations after treatment with tocilizumab have a high probability of association with @entity6912 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.
