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Population pharmacokinetics and pharmacogenetics of ritonavir-boosted darunavir in the presence of raltegravir or tenofovir disoproxil fumarate/emtricitabine in HIV-infected adults and the relationship with virological response: a sub-study of the NEAT001

dc.rights.licenseopenen_US
dc.contributor.authorDICKINSON, L.
dc.contributor.authorGURJAR, R.
dc.contributor.authorSTOHR, W.
dc.contributor.authorBONORA, S.
dc.contributor.authorOWEN, A.
dc.contributor.authorD'AVOLIO, A.
dc.contributor.authorCURSLEY, A.
dc.contributor.authorMOLINA, J. M.
dc.contributor.authorFAETKENHEUER, G.
dc.contributor.authorVANDEKERCKHOVE, L.
dc.contributor.authorDI PERRI, G.
dc.contributor.authorPOZNIAK, A.
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorRICHERT, Laura
dc.contributor.authorRAFFI, F.
dc.contributor.authorBOFFITO, M.
dc.date.accessioned2021-01-21T15:36:42Z
dc.date.available2021-01-21T15:36:42Z
dc.date.issued2020
dc.identifier.issn1460-2091 (Electronic) 0305-7453 (Linking)en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/25947
dc.description.abstractEnObjectives NEAT001/ANRS143 demonstrated non-inferiority of once-daily darunavir/ritonavir (800/100 mg) + twice-daily raltegravir (400 mg) versus darunavir/ritonavir + tenofovir disoproxil fumarate/emtricitabine (245/200 mg once daily) in treatment-naive patients. We investigated the population pharmacokinetics of darunavir, ritonavir, tenofovir and emtricitabine and relationships with demographics, genetic polymorphisms and virological failure. Methods Non-linear mixed-effects models (NONMEM v. 7.3) were applied to determine pharmacokinetic parameters and assess demographic covariates and relationships with SNPs (SLCO3A1, SLCO1B1, NR1I2, NR1I3, CYP3A5*3, CYP3A4*22, ABCC2, ABCC10, ABCG2 and SCL47A1). The relationship between model-predicted darunavir AUC0–24 and C24 with time to virological failure was evaluated by Cox regression. Results Of 805 enrolled, 716, 720, 347 and 361 were included in the darunavir, ritonavir, tenofovir and emtricitabine models, respectively (11% female, 83% Caucasian). No significant effect of patient demographics or SNPs was observed for darunavir or tenofovir apparent oral clearance (CL/F); coadministration of raltegravir did not influence darunavir or ritonavir CL/F. Ritonavir CL/F decreased by 23% in NR1I2 63396C>T carriers and emtricitabine CL/F was linearly associated with creatinine clearance (P<0.001). No significant relationship was demonstrated between darunavir AUC0–24 or C24 and time to virological failure [HR (95% CI): 2.28 (0.53–9.80), P=0.269; and 1.82 (0.61–5.41), P=0.279, respectively]. Conclusions Darunavir concentrations were unaltered in the presence of raltegravir and not associated with virological failure. Polymorphisms investigated had little impact on study-drug pharmacokinetics. Darunavir/ritonavir + raltegravir may be an appropriate option for patients experiencing NRTI-associated toxicity.
dc.language.isoENen_US
dc.subjectSISTM
dc.title.enPopulation pharmacokinetics and pharmacogenetics of ritonavir-boosted darunavir in the presence of raltegravir or tenofovir disoproxil fumarate/emtricitabine in HIV-infected adults and the relationship with virological response: a sub-study of the NEAT001
dc.title.alternativeJ Antimicrob Chemotheren_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1093/jac/dkz479en_US
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologieen_US
dc.identifier.pubmed31754703en_US
bordeaux.journalJournal of Antimicrobial Chemotherapyen_US
bordeaux.page628-639en_US
bordeaux.volume75en_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - U1219en_US
bordeaux.issue3en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.teamSISTM_BPH
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.identifierhal-03117913
hal.version1
hal.date.transferred2021-01-21T15:36:47Z
hal.exporttrue
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