PGx6633: FLAIR (GSK2190915) ADME Replication, Exploring the roles of UGT1A1 and UGT1A3

Trial description: GSK2190915 (fiboflapon) is a potent 5-lipoxygenase activating protein (FLAP) inhibitor being developed for the treatment of asthma. In early phase studies considerable inter-subject variability in pharmacokinetic (PK) exposure was observed. This finding motivated a pharmacogenetic investigation (PGx364) of 41 subjects from three phase 2A studies to see if genetic variants in several candidate genes could explain the PK variation. The alleles UGT1A1*28 and UGT1A3*2, which are highly correlated with each other, were found to be strongly associated with oral clearance. The previous investigation requires confirmation in an independent sample and, though from a biological perspective UGT1A3*2 is the more likely of the two alleles to be causing the PK exposure effect, resolving which of the two alleles is causal is not possible with the information in hand. The purpose of LPA117374 is to perform a pharmacogenetic analysis using samples independent of those in PGx364 to confirm if UGT1A1*28 and UGT1A3*2 are associated with oral clearance of GSK2190915. If the association is confirmed, an assessment of the association of UGT1A1*6 with oral clearance in Asian (Japanese) subjects will be undertaken. UGT1A1*6 is rarely described in Caucasians but relatively common in Japanese. UGT1A1*6 reduces the activity of UGT1A1 (as does UGT1A1*28) but UGT1A1*6 is not correlated with the presence of UGT1A3*2. If, in the Japanese subgroup, association with oral clearance is observed for UGT1A3*2, but not for UGT1A1*6, it will implicate UGT1A3*2 as the causal allele. The distribution of oral clearance in approximately 500 subjects of all race groups will be assessed and appropriate transformations will be applied to manage non-normality and extreme outliers, if present. The effects of potential covariates will be examined and those found to be significantly associated with oral clearance will be incorporated into the statistical models used to evaluate genetic marker associations. UGT1A1*28, UGT1A3*2, and UGT1A1*6 (if analyzed) will be coded as numeric variables reflecting the presence of 0, 1, or 2 copies of the allele of interest. Analysis of covariance will be used to determine if either marker has a significant effect on oral clearance at p<0.05. If neither marker is found to be significantly associated with oral clearance, no further analyses will be pursued. If either marker is significantly associated with oral clearance, then assessments of UGT1A1*28 and UGT1A3*2 will be conducted with the three racial subgroups: whites, African Americans, and Asians (Japanese) to investigate whether the effect of the alleles is the same within each of them. In addition, UGT1A1*6 will be investigated in the Japanese subgroup to compare its effects on oral clearance with those of UGT1A3*2.