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

Media type: E-Article
Title: 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
Contributor: Dickinson, Laura; Gurjar, Rohan; Stöhr, Wolfgang; Bonora, Stefano; Owen, Andrew; D’Avolio, Antonio; Cursley, Adam; Molina, Jean-Michel; Fäetkenheuer, Gerd; Vandekerckhove, Linos; Di Perri, Giovanni; Pozniak, Anton; Richert, Laura; Raffi, François; Boffito, Marta; Dedes, Nikos; Chene, Genevieve; Richert, Laura; Allavena, Clotilde; Raffi, Francois; Autran, Brigitte; Antinori, Andrea; Bucciardini, Raffaella; Vella, Stefano; [...]
Published: Oxford University Press (OUP), 2020
Published in: Journal of Antimicrobial Chemotherapy
Extent: 628-639
Language: English
DOI: 10.1093/jac/dkz479
ISSN: 0305-7453; 1460-2091
Keywords: Infectious Diseases ; Pharmacology (medical) ; Pharmacology ; Microbiology (medical)
Abstract: <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Objectives</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>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&gt;T carriers and emtricitabine CL/F was linearly associated with creatinine clearance (P&lt;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].</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>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.</jats:p> </jats:sec>
Description: <jats:title>Abstract</jats:title>
<jats:sec>
<jats:title>Objectives</jats:title>
<jats:p>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.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Methods</jats:title>
<jats:p>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.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Results</jats:title>
<jats:p>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&gt;T carriers and emtricitabine CL/F was linearly associated with creatinine clearance (P&lt;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].</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Conclusions</jats:title>
<jats:p>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.</jats:p>
</jats:sec>
Footnote:
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