Advanced search
1 file | 376.21 KB Add to list

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

Author
Organization
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 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.
Keywords
EMTRICITABINE, PLASMA, LOPINAVIR, POLYMORPHISMS, ASSOCIATION, TRANSPORTER, METFORMIN, VARIANT, MEMBERS, MATE1

Downloads

  • (...).pdf
    • full text
    • |
    • UGent only
    • |
    • PDF
    • |
    • 376.21 KB

Citation

Please use this url to cite or link to this publication:

MLA
Dickinson, Laura, et al. “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, vol. 75, no. 3, 2020, pp. 628–39, doi:10.1093/jac/dkz479.
APA
Dickinson, L., Gurjar, R., Stöhr, W., Bonora, S., Owen, A., D’Avolio, A., … Focà, E. (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), 628–639. https://doi.org/10.1093/jac/dkz479
Chicago author-date
Dickinson, Laura, Rohan Gurjar, Wolfgang Stöhr, Stefano Bonora, Andrew Owen, Antonio D’Avolio, Adam Cursley, et al. 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): 628–39. https://doi.org/10.1093/jac/dkz479.
Chicago author-date (all authors)
Dickinson, Laura, Rohan Gurjar, Wolfgang Stöhr, Stefano Bonora, Andrew Owen, Antonio D’Avolio, Adam Cursley, Jean-Michel Molina, Gerd Fäetkenheuer, Linos Vandekerckhove, Giovanni Di Perri, Anton Pozniak, Laura Richert, François Raffi, Marta Boffito, Nikos Dedes, Genevieve Chene, Laura Richert, Clotilde Allavena, Francois Raffi, Brigitte Autran, Andrea Antinori, Raffaella Bucciardini, Stefano Vella, Andrzej Horban, Jose Arribas, Abdel G Babiker, Marta Boffito, the NEAT001/ANRS143 Study Group, Deenan Pillay, Anton Pozniak, Xavier Franquet, Siegfried Schwarze, Jesper Grarup, Genevieve Chene, Aurelie Fischer, Laura Richert, Cedrick Wallet, Francois Raffi, Alpha Diallo, Jean-Michel Molina, Juliette Saillard, Christiane Moecklinghoff, Hans-Jurgen Stellbrink, Stefano Vella, Remko VanLeeuwen, Jose Gatell, Eric Sandstrom, Markus Flepp, Abdel G Babiker, Fiona Ewings, Elizabeth C George, Fleur Hudson, Anton Pozniak, Gillian Pearce, Romina Quercia, Felipe Rogatto, Randi Leavitt, Bach-Yen Nguyen, Tim Peto, Frank Goebel, Simone Marcotullio, Veronica Miller, Peter Sasieni, Clotilde Allavena, François Raffi, Stefano Vella, Anton Pozniak, Geneviève Chêne, Fabien Arnault, Céline Boucherie, Aurélie Fischer, Delphine Jean, Virginie Paniego, Felasoa Paraina, Laura Richert, Elodie Rouch, Christine Schwimmer, Malika Soussi, Audrey Taieb, Monique Termote, Guillaume Touzeau, Cédrick Wallet, AbdelG Babiker, Adam Cursley, Wendy Dodds, Fiona Ewings, Elizabeth C George, Anne Hoppe, Fleur Hudson, Ischa Kummeling, Filippo Pacciarini, Nick Paton, Charlotte Russell, Kay Taylor, Denise Ward, Bitten Aagaard, Marius Eid, Daniela Gey, Birgitte GramJensen, Marie-Louise Jakobsen, Per O Jansson, Karoline Jensen, Zillah MariaJoensen, Ellen MoseholmLarsen, Christiane Pahl, Mary Pearson, Birgit Riis Nielsen, Søren Stentoft Reilev, Ilse Christ, Desiree Lathouwers, Corry Manting, Remko Van Leeuwen, Alpha Diallo, BienvenuYves Mendy, Annie Metro, Juliette Saillard, Sandrine Couffin-Cadiergues, Anne-Laure Knellwolf, Lucia Palmisiano, Esther Aznar, Cristina Barea, Manuel Cotarelo, Herminia Esteban, Iciar Girbau, Beatriz Moyano, Miriam Ramirez, Carmen Saiz, Isabel Sanchez, Maria Yllescas, Andrea Binelli, Valentina Colasanti, Maurizio Massella, Lucia Palmisiano, Olga Anagnostou, Vicky Gioukari, Giota Touloumi, Brigitte Schmied, Armin Rieger, Norbert Vetter, Stephane DeWit, Eric Florence, Linos Vandekerckhove, Jan Gerstoft, Lars Mathiesen, Christine Katlama, Andre Cabie, Antoine Cheret, Michel Dupon, Jade Ghosn, Pierre-Marie Girard, Cécile Goujard, Yves Lévy, Jean-Michel Molina, Philippe Morlat, Didier Neau, Martine Obadia, Philippe Perre, Lionel Piroth, Jacques Reynes, Pierre Tattevin, Francois Raffi, Jean Marie Ragnaud, Laurence Weiss, Yazdanpanah Yazdan, Patrick Yeni, David Zucman, Stefan Esser, Gerd Fätkenheuer, Christian Hoffmann, Heiko Jessen, Jürgen Rockstroh, Reinhold Schmidt, Christoph Stephan, Stefan Unger, Angelos Hatzakis, George L Daikos, Antonios Papadopoulos, Athamasios Skoutelis, Denes Banhegyi, Paddy Mallon, Fiona Mulcahy, Andrea Antinori, Massimo Andreoni, Stefano Bonora, Francesco Castelli, Antonella D’ArminioMonforte, Giovanni DiPerri, Massimo Galli, Adriano Lazzarin, Francesco Mazzotta, Carlo Torti, Vincenzo Vullo, Jan Prins, Clemens Richter, Dominique Verhagen, Arne VanEeden, Andrzej Horban, Manuela Doroana, Francisco Antunes, Fernando Maltez, Rui Sarmento-Castro, Juan Gonzalez Garcia, José López Aldeguer, Bonaventura Clotet, Pere Domingo, Jose M Gatell, Hernando Knobel, Manuel Marquez, Martin PilarMiralles, Joaquin Portilla, Vicente Soriano, MariaJesus Tellez, Anders Thalme, Anders Blaxhult, Magnus Gisslen, Alan Winston, Julie Fox, Mark Gompels, Elbushra Herieka, Margaret Johnson, Clifford Leen, Anton Pozniak, Alastair Teague, Ian Williams, MarkAlastair Boyd, Jesper Grarup, Per O Jansson, Nina Friis Møller, Ellen Frøsig MoseholmLarsen, Philippe Morlat, Lionel Piroth, Vincent LeMoing, Ferdinand W N M Wit, Justyna Kowalska, Juan Berenguer, Santiago Moreno, Nicolas J Müller, Estée Török, Frank Post, Brian Angus, Vincent Calvez, Charles Boucher, Simon Collins, David Dunn, Sidonie Lambert, Anne-Geneviève Marcelin, Carlo Federico Perno, Deenan Pillay, Ellen White, Marta Boffito, Adriana Ammassari, Andrea Antinori, Wolfgang Stöhr, Brigitte Autran, Reinhold Ernst Schmidt, Michal Odermarsky, Colette Smith, Rodolphe Thiébaut, Jose Arribas, Jose Ignacio Bernardino DeLaSerna, Antonella Castagna, Stephane De Wit, Xavier Franquet, Hans-Jackob Furrer, Christine Katlama, Amanda Mocroft, Peter Reiss, Raffaella Bucciardini, Nikos Dedes, Vincenzo Fragola, Elizabeth C George, Marco Lauriola, Rita Murri, Pythia Nieuwkerk, Bruno Spire, Alain Volny-Anne, Brian West, Hélène Amieva, Andrea Antinori, JosepMaria Llibre Codina, Laura Richert, Wolfgang Stöhr, Alan Winston, Francesco Castelli, Marco Braggion, and Emanuele Focà. 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): 628–639. doi:10.1093/jac/dkz479.
Vancouver
1.
Dickinson L, Gurjar R, Stöhr W, Bonora S, Owen A, D’Avolio A, et al. 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. 2020;75(3):628–39.
IEEE
[1]
L. Dickinson et al., “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, vol. 75, no. 3, pp. 628–639, 2020.
@article{8637375,
  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 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.},
  author       = {Dickinson, Laura and Gurjar, Rohan and Stöhr, Wolfgang and Bonora, Stefano and Owen, Andrew and D’Avolio, Antonio and Cursley, Adam and Molina, Jean-Michel and Fäetkenheuer, Gerd and Vandekerckhove, Linos and Di Perri, Giovanni and Pozniak, Anton and Richert, Laura and Raffi, François and Boffito, Marta and Dedes, Nikos and Chene, Genevieve and Richert, Laura and Allavena, Clotilde and Raffi, Francois and Autran, Brigitte and Antinori, Andrea and Bucciardini, Raffaella and Vella, Stefano and Horban, Andrzej and Arribas, Jose and Babiker, Abdel G and Boffito, Marta and NEAT001/ANRS143 Study Group, the and Pillay, Deenan and Pozniak, Anton and Franquet, Xavier and Schwarze, Siegfried and Grarup, Jesper and Chene, Genevieve and Fischer, Aurelie and Richert, Laura and Wallet, Cedrick and Raffi, Francois and Diallo, Alpha and Molina, Jean-Michel and Saillard, Juliette and Moecklinghoff, Christiane and Stellbrink, Hans-Jurgen and Vella, Stefano and VanLeeuwen, Remko and Gatell, Jose and Sandstrom, Eric and Flepp, Markus and Babiker, Abdel G and Ewings, Fiona and George, Elizabeth C and Hudson, Fleur and Pozniak, Anton and Pearce, Gillian and Quercia, Romina and Rogatto, Felipe and Leavitt, Randi and Nguyen, Bach-Yen and Peto, Tim and Goebel, Frank and Marcotullio, Simone and Miller, Veronica and Sasieni, Peter and Allavena, Clotilde and Raffi, François and Vella, Stefano and Pozniak, Anton and Chêne, Geneviève and Arnault, Fabien and Boucherie, Céline and Fischer, Aurélie and Jean, Delphine and Paniego, Virginie and Paraina, Felasoa and Richert, Laura and Rouch, Elodie and Schwimmer, Christine and Soussi, Malika and Taieb, Audrey and Termote, Monique and Touzeau, Guillaume and Wallet, Cédrick and Babiker, AbdelG and Cursley, Adam and Dodds, Wendy and Ewings, Fiona and George, Elizabeth C and Hoppe, Anne and Hudson, Fleur and Kummeling, Ischa and Pacciarini, Filippo and Paton, Nick and Russell, Charlotte and Taylor, Kay and Ward, Denise and Aagaard, Bitten and Eid, Marius and Gey, Daniela and GramJensen, Birgitte and Jakobsen, Marie-Louise and Jansson, Per O and Jensen, Karoline and MariaJoensen, Zillah and MoseholmLarsen, Ellen and Pahl, Christiane and Pearson, Mary and Nielsen, Birgit Riis and Reilev, Søren Stentoft and Christ, Ilse and Lathouwers, Desiree and Manting, Corry and Van Leeuwen, Remko and Diallo, Alpha and Mendy, BienvenuYves and Metro, Annie and Saillard, Juliette and Couffin-Cadiergues, Sandrine and Knellwolf, Anne-Laure and Palmisiano, Lucia and Aznar, Esther and Barea, Cristina and Cotarelo, Manuel and Esteban, Herminia and Girbau, Iciar and Moyano, Beatriz and Ramirez, Miriam and Saiz, Carmen and Sanchez, Isabel and Yllescas, Maria and Binelli, Andrea and Colasanti, Valentina and Massella, Maurizio and Palmisiano, Lucia and Anagnostou, Olga and Gioukari, Vicky and Touloumi, Giota and Schmied, Brigitte and Rieger, Armin and Vetter, Norbert and DeWit, Stephane and Florence, Eric and Vandekerckhove, Linos and Gerstoft, Jan and Mathiesen, Lars and Katlama, Christine and Cabie, Andre and Cheret, Antoine and Dupon, Michel and Ghosn, Jade and Girard, Pierre-Marie and Goujard, Cécile and Lévy, Yves and Molina, Jean-Michel and Morlat, Philippe and Neau, Didier and Obadia, Martine and Perre, Philippe and Piroth, Lionel and Reynes, Jacques and Tattevin, Pierre and Raffi, Francois and Ragnaud, Jean Marie and Weiss, Laurence and Yazdan, Yazdanpanah and Yeni, Patrick and Zucman, David and Esser, Stefan and Fätkenheuer, Gerd and Hoffmann, Christian and Jessen, Heiko and Rockstroh, Jürgen and Schmidt, Reinhold and Stephan, Christoph and Unger, Stefan and Hatzakis, Angelos and Daikos, George L and Papadopoulos, Antonios and Skoutelis, Athamasios and Banhegyi, Denes and Mallon, Paddy and Mulcahy, Fiona and Antinori, Andrea and Andreoni, Massimo and Bonora, Stefano and Castelli, Francesco and D’ArminioMonforte, Antonella and DiPerri, Giovanni and Galli, Massimo and Lazzarin, Adriano and Mazzotta, Francesco and Torti, Carlo and Vullo, Vincenzo and Prins, Jan and Richter, Clemens and Verhagen, Dominique and VanEeden, Arne and Horban, Andrzej and Doroana, Manuela and Antunes, Francisco and Maltez, Fernando and Sarmento-Castro, Rui and Gonzalez Garcia, Juan and Aldeguer, José López and Clotet, Bonaventura and Domingo, Pere and Gatell, Jose M and Knobel, Hernando and Marquez, Manuel and PilarMiralles, Martin and Portilla, Joaquin and Soriano, Vicente and Tellez, MariaJesus and Thalme, Anders and Blaxhult, Anders and Gisslen, Magnus and Winston, Alan and Fox, Julie and Gompels, Mark and Herieka, Elbushra and Johnson, Margaret and Leen, Clifford and Pozniak, Anton and Teague, Alastair and Williams, Ian and Boyd, MarkAlastair and Grarup, Jesper and Jansson, Per O and Møller, Nina Friis and MoseholmLarsen, Ellen Frøsig and Morlat, Philippe and Piroth, Lionel and LeMoing, Vincent and Wit, Ferdinand W N M and Kowalska, Justyna and Berenguer, Juan and Moreno, Santiago and Müller, Nicolas J and Török, Estée and Post, Frank and Angus, Brian and Calvez, Vincent and Boucher, Charles and Collins, Simon and Dunn, David and Lambert, Sidonie and Marcelin, Anne-Geneviève and Perno, Carlo Federico and Pillay, Deenan and White, Ellen and Boffito, Marta and Ammassari, Adriana and Antinori, Andrea and Stöhr, Wolfgang and Autran, Brigitte and Schmidt, Reinhold Ernst and Odermarsky, Michal and Smith, Colette and Thiébaut, Rodolphe and Arribas, Jose and DeLaSerna, Jose Ignacio Bernardino and Castagna, Antonella and De Wit, Stephane and Franquet, Xavier and Furrer, Hans-Jackob and Katlama, Christine and Mocroft, Amanda and Reiss, Peter and Bucciardini, Raffaella and Dedes, Nikos and Fragola, Vincenzo and George, Elizabeth C and Lauriola, Marco and Murri, Rita and Nieuwkerk, Pythia and Spire, Bruno and Volny-Anne, Alain and West, Brian and Amieva, Hélène and Antinori, Andrea and Llibre Codina, JosepMaria and Richert, Laura and Stöhr, Wolfgang and Winston, Alan and Castelli, Francesco and Braggion, Marco and Focà, Emanuele},
  issn         = {0305-7453},
  journal      = {JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY},
  keywords     = {EMTRICITABINE,PLASMA,LOPINAVIR,POLYMORPHISMS,ASSOCIATION,TRANSPORTER,METFORMIN,VARIANT,MEMBERS,MATE1},
  language     = {eng},
  number       = {3},
  pages        = {628--639},
  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},
  url          = {http://dx.doi.org/10.1093/jac/dkz479},
  volume       = {75},
  year         = {2020},
}

Altmetric
View in Altmetric
Web of Science
Times cited: