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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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; 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; NEAT001/ANRS143 Study Group; Dedes, Nikos; Chene, Genevieve; Richert, Laura; Grarup, Jesper; Aagaard, Bitten; Eid, Marius; Gey, Daniela; Jensen, Birgitte Gram; Grarup, Jesper; Jakobsen, Marie Louise; Jansson, Per O; Jensen, Karoline; Joensen, Zillah Maria; Larsen, Ellen Moseholm; Pahl, Christiane; Pearson, Mary; Nielsen, Birgit Riis; Reilev, Søren Stentoft; Gerstoft, Jan; Mathiesen, Lars; Friis-Møller, Nina; Larsen, Ellen Frøsig Moseholm.
In: Journal of Antimicrobial Chemotherapy, Vol. 75, 2020, p. 628-639.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - 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
T2 - a sub-study of the NEAT001/ANRS143 randomized trial
AU - Dickinson, Laura
AU - Gurjar, Rohan
AU - Stöhr, Wolfgang
AU - Bonora, Stefano
AU - Owen, Andrew
AU - D'Avolio, Antonio
AU - Cursley, Adam
AU - Molina, Jean-Michel
AU - Fäetkenheuer, Gerd
AU - Vandekerckhove, Linos
AU - Di Perri, Giovanni
AU - Pozniak, Anton
AU - Richert, Laura
AU - Raffi, François
AU - Boffito, Marta
AU - NEAT001/ANRS143 Study Group
AU - Dedes, Nikos
AU - Chene, Genevieve
AU - Richert, Laura
AU - Grarup, Jesper
AU - Aagaard, Bitten
AU - Eid, Marius
AU - Gey, Daniela
AU - Jensen, Birgitte Gram
AU - Grarup, Jesper
AU - Jakobsen, Marie Louise
AU - Jansson, Per O
AU - Jensen, Karoline
AU - Joensen, Zillah Maria
AU - Larsen, Ellen Moseholm
AU - Pahl, Christiane
AU - Pearson, Mary
AU - Nielsen, Birgit Riis
AU - Reilev, Søren Stentoft
AU - Gerstoft, Jan
AU - Mathiesen, Lars
AU - Friis-Møller, Nina
AU - Larsen, Ellen Frøsig Moseholm
N1 - © The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.
PY - 2020
Y1 - 2020
N2 - 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 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.
AB - 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 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.
U2 - 10.1093/jac/dkz479
DO - 10.1093/jac/dkz479
M3 - Journal article
C2 - 31754703
VL - 75
SP - 628
EP - 639
JO - Journal of Antimicrobial Chemotherapy
JF - Journal of Antimicrobial Chemotherapy
SN - 0305-7453
ER -
ID: 257659761