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

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Dickinson, L ORCID: 0000-0001-5557-9396, Gurjar, R, Stöhr, W, Bonora, S, Owen, A ORCID: 0000-0002-9819-7651, D'Avolio, A, Cursley, A, Molina, JM, Fäetkenheuer, G, Vandekerckhove, L et al (show 90 more authors) , Di Perri, G, Pozniak, A, Richert, L, Raffi, F, Boffito, M, Dedes, N, Chene, G, Allavena, C, Autran, B, Antinori, A, Bucciardini, R, Vella, S, Horban, A, Arribas, J, Babiker, AG, Pillay, D, Franquet, X, Schwarze, S, Grarup, J, Fischer, A, Wallet, C, Diallo, A, Saillard, J, Moecklinghoff, C, Stellbrink, HJ, Vanleeuwen, R, Gatell-Artigas, JM, Sandstrom, E, Flepp, M, Ewings, F, George, EC, Hudson, F, Pearce, G, Quercia, R, Rogatto, F, Leavitt, R, Nguyen, BY, Peto, T, Goebel, F, Marcotullio, S, Miller, V, Sasieni, P, Arnault, F, Boucherie, C, Jean, D, Paniego, V, Paraina, F, Rouch, E, Schwimmer, C, Soussi, M, Taieb, A, Termote, M, Touzeau, G, Babiker, AG, Dodds, W, Hoppe, A, Kummeling, I, Pacciarini, F, Paton, N, Russell, C, Taylor, K, Ward, D, Aagaard, B, Eid, M, Gey, D, Gramjensen, B, Jakobsen, ML, Jansson, PO, Jensen, K, Mariajoensen, Z, Moseholmlarsen, E, Pahl, C, Pearson, M, Nielsen, BR, Reilev, SS, Christ, I, Lathouwers, D, Manting, C, Van Leeuwen, R, Mendy, BY, Metro, A, Couffin-Cadiergues, S, Knellwolf, AL, Palmisiano, L, Aznar, E, Barea, C, Cotarelo, M, Esteban, H, Girbau, I and Moyano, B (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. ISSN 0305-7453, 1460-2091

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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<inf>0-24</inf> and C<inf>24</inf> 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<inf>0-24</inf> or C<inf>24</inf> 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:	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:	22 Jan 2026 12:24
DOI:	10.1093/jac/dkz479
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3064465
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