TY - JOUR
T1 - Impact of UGT1A1 polymorphisms on Raltegravir and its glucuronide plasma concentrations in a cohort of HIV-1 infected patients
AU - Belkhir, Leïla
AU - Seguin-Devaux, Carole
AU - Elens, Laure
AU - Pauly, Caroline
AU - Gengler, Nicolas
AU - Schneider, Serge
AU - Ruelle, Jean
AU - Haufroid, Vincent
AU - Vandercam, Bernard
N1 - Funding Information:
Competing Interests: This work was supported by the Fondation Saint-Luc (Cliniques universitaires Saint-Luc, Belgium) and with the Fonds Pierre et Colette Bauchau (UCL, Belgium). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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 UGT1A1∗1/∗1 while 50% (n = 48) and 6% (n = 6) were UGT1A1∗28 and UGT1A1∗36 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 UGT1A1∗1/∗1, UGT1A1∗28 and UGT1A1∗36 carriers, respectively. Only the difference between UGT1A1∗1/∗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 UGT1A1∗1/∗1, UGT1A1∗28 and UGT1A1∗36 carriers, respectively. Only the difference between UGT1A1∗1/∗1 and∗28 carriers was statistically significant (p = 0.004) with an allele-dependent effect: UGT1A1∗28 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 UGT1A1∗28 polymorphism has a significant impact on RAL metabolism: UGT1A1∗28 carriers being characterized by higher [RAL]plasma and lower MR.
AB - 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 UGT1A1∗1/∗1 while 50% (n = 48) and 6% (n = 6) were UGT1A1∗28 and UGT1A1∗36 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 UGT1A1∗1/∗1, UGT1A1∗28 and UGT1A1∗36 carriers, respectively. Only the difference between UGT1A1∗1/∗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 UGT1A1∗1/∗1, UGT1A1∗28 and UGT1A1∗36 carriers, respectively. Only the difference between UGT1A1∗1/∗1 and∗28 carriers was statistically significant (p = 0.004) with an allele-dependent effect: UGT1A1∗28 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 UGT1A1∗28 polymorphism has a significant impact on RAL metabolism: UGT1A1∗28 carriers being characterized by higher [RAL]plasma and lower MR.
UR - http://www.scopus.com/inward/record.url?scp=85046843185&partnerID=8YFLogxK
U2 - 10.1038/s41598-018-25803-z
DO - 10.1038/s41598-018-25803-z
M3 - Article
C2 - 29743555
AN - SCOPUS:85046843185
SN - 2045-2322
VL - 8
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 7359
ER -