Gurjar, Rohan, Dickinson, Laura, Carr, Daniel, Stohr, Wolfgang ORCID: 0000-0002-6533-2888, Bonora, Stefano, Owen, Andrew ORCID: 0000-0002-9819-7651, D'Avolio, Antonio, Cursley, Adam, De Castro, Nathalie, Fatkenheuer, Gerd, Vandekerckhove, Linos, Di Perri, Giovanni, Pozniak, Anton, Schwimmer, Christine, Raffi, Francois and Boffito, Marta . Influence of UGT1A1 and SLC22A6 polymorphisms on the population pharmacokinetics and pharmacodynamics of raltegravir in HIV-infected adults: a NEAT001/ANRS143 sub-study. Pharmacogenomics J.. LONDON: SPRINGERNATURE. ISSN 1473-1150

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Gurjar, RohanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dickinson, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carr, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stohr, WolfgangUNSPECIFIEDorcid.org/0000-0002-6533-2888UNSPECIFIED
Bonora, StefanoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Owen, AndrewUNSPECIFIEDorcid.org/0000-0002-9819-7651UNSPECIFIED
D'Avolio, AntonioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cursley, AdamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Castro, NathalieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fatkenheuer, GerdUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vandekerckhove, LinosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Di Perri, GiovanniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pozniak, AntonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwimmer, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Raffi, FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boffito, MartaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-695549
DOI: 10.1038/s41397-022-00293-5
Journal or Publication Title: Pharmacogenomics J.
Publisher: SPRINGERNATURE
Place of Publication: LONDON
ISSN: 1473-1150
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
INTEGRASE INHIBITOR; EFAVIRENZ; PLASMA; PHARMACOGENETICS; VARIABILITY; TENOFOVIR/EMTRICITABINE; EMTRICITABINE; PHARMACOLOGY; INDIVIDUALS; ATAZANAVIRMultiple languages
Genetics & Heredity; Pharmacology & PharmacyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69554

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