Dickinson, Laura, Gurjar, Rohan, Stoehr, Wolfgang, Bonora, Stefano, Owen, Andrew, D'Avolio, Antonio, Cursley, Adam, Molina, Jean-Michel, Faeetkenheuer, Gerd, Vandekerckhove, Linos, Di Perri, Giovanni, Pozniak, Anton, Richert, Laura, Raffi, Francois and Boffito, Marta (2020). 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/ANRS143 randomized trial. J. Antimicrob. Chemother., 75 (3). S. 628 - 640. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2091
Full text not available from this repository.Abstract
Objectives: 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 AUC(0-24) and C-24 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 AUC(0-24) or C-24 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.
| Item Type: | Journal Article | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| URN: | urn:nbn:de:hbz:38-343328 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DOI: | 10.1093/jac/dkz479 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Journal or Publication Title: | J. Antimicrob. Chemother. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Volume: | 75 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Number: | 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Page Range: | S. 628 - 640 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Date: | 2020 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Publisher: | OXFORD UNIV PRESS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Place of Publication: | OXFORD | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ISSN: | 1460-2091 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Language: | English | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Faculty: | Unspecified | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Divisions: | Unspecified | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Subjects: | no entry | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| URI: | http://kups.ub.uni-koeln.de/id/eprint/34332 |
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