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


Dickinson, Laura ORCID: 0000-0001-5557-9396, Gurjar, Rohan, Stoehr, Wolfgang, Bonora, Stefano, Owen, Andrew ORCID: 0000-0002-9819-7651, D'Avolio, Antonio, Cursley, Adam, Molina, Jean-Michel, Faeetkenheuer, Gerd, Vandekerckhove, Linos et al (show 5 more authors) (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. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 75 (3). pp. 628-639.

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Abstract

<h4>Objectives</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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].<h4>Conclusions</h4>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: Article
Uncontrolled Keywords: NEAT001/ANRS143 Study Group, Humans, HIV Infections, Ritonavir, Anti-HIV Agents, Viral Load, Pharmacogenetics, Adult, Female, Male, Tenofovir, Emtricitabine, Darunavir, Raltegravir Potassium, Liver-Specific Organic Anion Transporter 1, Multidrug Resistance-Associated Protein 2, Constitutive Androstane Receptor
Depositing User: Symplectic Admin
Date Deposited: 03 Dec 2019 08:36
Last Modified: 19 Jan 2023 00:17
DOI: 10.1093/jac/dkz479
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3064465
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