TY  - INPR
TI  - Influence of UGT1A1 and SLC22A6 polymorphisms on the population pharmacokinetics and pharmacodynamics of raltegravir in HIV-infected adults: a NEAT001/ANRS143 sub-study
Y1  - 2022/10/20/
AV  - public
N1  - This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article?s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article?s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
N2  - Using concentration-time data from the NEAT001/ARNS143 study (single sample at week 4 and 24), we determined raltegravir pharmacokinetic parameters using nonlinear mixed effects modelling (NONMEM v.7.3; 602 samples from 349 patients) and investigated the influence of demographics and SNPs (SLC22A6 and UGT1A1) on raltegravir pharmacokinetics and pharmacodynamics. Demographics and SNPs did not influence raltegravir pharmacokinetics and no significant pharmacokinetic/pharmacodynamic relationships were observed. At week 96, UGT1A1*28/*28 was associated with lower virological failure (p?=?0.012), even after adjusting for baseline CD4 count (p?=?0.048), but not when adjusted for baseline HIV-1 viral load (p?=?0.082) or both (p?=?0.089). This is the first study to our knowledge to assess the influence of SNPs on raltegravir pharmacodynamics. The lack of a pharmacokinetic/pharmacodynamic relationship is potentially an artefact of raltegravir?s characteristic high inter and intra-patient variability and also suggesting single time point sampling schedules are inadequate to thoroughly assess the influence of SNPs on raltegravir pharmacokinetics.
ID  - discovery10158094
PB  - Springer Science and Business Media LLC
UR  - https://doi.org/10.1038/s41397-022-00293-5
SN  - 1470-269X
JF  - The Pharmacogenomics Journal
A1  - Gurjar, Rohan
A1  - Dickinson, Laura
A1  - Carr, Daniel
A1  - Stöhr, Wolfgang
A1  - Bonora, Stefano
A1  - Owen, Andrew
A1  - D'Avolio, Antonio
A1  - Cursley, Adam
A1  - De Castro, Nathalie
A1  - Fätkenheuer, Gerd
A1  - Vandekerckhove, Linos
A1  - Di Perri, Giovanni
A1  - Pozniak, Anton
A1  - Schwimmer, Christine
A1  - Raffi, François
A1  - Boffito, Marta
A1  - NEAT001/ANRS143 Study Group
KW  - Clinical pharmacology
KW  -  Pharmacogenetics
KW  -  Pharmacokinetics
ER  -