Impact of UGT1A1 polymorphisms on Raltegravir and its glucuronide plasma concentrations in a cohort of HIV-1 infected patients.

The aim of this study was to evaluate the effect of UGT1A1 polymorphisms on Raltegravir (RAL) and its metabolite RAL-glucuronide trough plasma concentrations ([RAL]plasma and [RAL-glu]plasma) and on the metabolic ratio (MR): [RAL-glu]plasma/[RAL]plasma. UGT1A1 genotyping was performed on 96 patients. 44% (n = 42) were homozygous UGT1A11/1 while 50% (n = 48) and 6% (n = 6) were UGT1A128 and UGT1A136 carriers, respectively. The median concentration and interquartile range (IQR) of [RAL]plasma were 88.5 ng/ml (41.0-236), 168 ng/ml (85.8-318) and 92.5 ng/ml (36.4-316) for UGT1A11/1, UGT1A128 and UGT1A136 carriers, respectively. Only the difference between UGT1A11/1 and 28 carriers was statistically significant (p = 0.022). The median MR (IQR) were 5.8 (3-10), 2.9 (1.6-5.3) and 3.2 (1.7-5.9) for UGT1A11/1, UGT1A128 and UGT1A136 carriers, respectively. Only the difference between UGT1A11/*1 and 28 carriers was statistically significant (p = 0.004) with an allele-dependent effect: UGT1A128 homozygous having lower MR than heterozygous carriers who show lower MR compared to 1/1. Except for the sensation of fatigue, this PK effect did not correlate with clinical adverse events or biological abnormalities. In Conclusion, we demonstrate that UGT1A128 polymorphism has a significant impact on RAL metabolism: UGT1A128 carriers being characterized by higher [RAL]plasma and lower MR.