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
Authors: 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 , Allavena Clotilde , Raffi Francois , Autran Brigitte , Antinori Andrea , Bucciardini Raffaella , Vella Stefano , Horban Andrzej , Arribas Jose , Babiker Abdel G , Boffito Marta , Pillay Deenan , Pozniak Anton , Franquet Xavier , Schwarze Siegfried , Grarup Jesper , Chene Genevieve , Fischer Aurelie , Richert Laura , Wallet Cedrick , Raffi Francois , Diallo Alpha , Molina Jean-Michel , Saillard Juliette , Moecklinghoff Christiane , Stellbrink Hans-Jurgen , Vella Stefano , VanLeeuwen Remko , Gatell Jose , Sandstrom Eric , Flepp Markus , Babiker Abdel G , Ewings Fiona , George Elizabeth C , Hudson Fleur , Pozniak Anton , Pearce Gillian , Quercia Romina , Rogatto Felipe , Leavitt Randi , Nguyen Bach-Yen , Peto Tim , Goebel Frank , Marcotullio Simone , Miller Veronica , Sasieni Peter , Allavena Clotilde , Raffi François , Vella Stefano , Pozniak Anton , Chêne Geneviève , Arnault Fabien , Boucherie Céline , Fischer Aurélie , Jean Delphine , Paniego Virginie , Paraina Felasoa , Richert Laura , Rouch Elodie , Schwimmer Christine , Soussi Malika , Taieb Audrey , Termote Monique , Touzeau Guillaume , Wallet Cédrick , Babiker AbdelG , Cursley Adam , Dodds Wendy , Ewings Fiona , George Elizabeth C , Hoppe Anne , Hudson Fleur , Kummeling Ischa , Pacciarini Filippo , Paton Nick , Russell Charlotte , Taylor Kay , Ward Denise , Aagaard Bitten , Eid Marius , Gey Daniela , GramJensen Birgitte , Jakobsen Marie-Louise , Jansson Per O , Jensen Karoline , MariaJoensen Zillah , MoseholmLarsen Ellen , Pahl Christiane , Pearson Mary , Nielsen Birgit Riis , Reilev Søren Stentoft , Christ Ilse , Lathouwers Desiree , Manting Corry , Van Leeuwen Remko , Diallo Alpha , Mendy BienvenuYves , Metro Annie , Saillard Juliette , Couffin-Cadiergues Sandrine , Knellwolf Anne-Laure , Palmisiano Lucia , Aznar Esther , Barea Cristina , Cotarelo Manuel , Esteban Herminia , Girbau Iciar , Moyano Beatriz , Ramirez Miriam , Saiz Carmen , Sanchez Isabel , Yllescas Maria , Binelli Andrea , Colasanti Valentina , Massella Maurizio , Palmisiano Lucia , Anagnostou Olga , Gioukari Vicky , Touloumi Giota , Schmied Brigitte , Rieger Armin , Vetter Norbert , DeWit Stephane , Florence Eric , Vandekerckhove Linos , Gerstoft Jan , Mathiesen Lars , Katlama Christine , Cabie Andre , Cheret Antoine , Dupon Michel , Ghosn Jade , Girard Pierre-Marie , Goujard Cécile , Lévy Yves , Molina Jean-Michel , Morlat Philippe , Neau Didier , Obadia Martine , Perre Philippe , Piroth Lionel , Reynes Jacques , Tattevin Pierre , Raffi Francois , Ragnaud Jean Marie , Weiss Laurence , Yazdan Yazdanpanah , Yeni Patrick , Zucman David , Esser Stefan , Fätkenheuer Gerd , Hoffmann Christian , Jessen Heiko , Rockstroh Jürgen , Schmidt Reinhold , Stephan Christoph , Unger Stefan , Hatzakis Angelos , Daikos George L , Papadopoulos Antonios , Skoutelis Athamasios , Banhegyi Denes , Mallon Paddy , Mulcahy Fiona , Antinori Andrea , Andreoni Massimo , Bonora Stefano , Castelli Francesco , D’ArminioMonforte Antonella , DiPerri Giovanni , Galli Massimo , Lazzarin Adriano , Mazzotta Francesco , Torti Carlo , Vullo Vincenzo , Prins Jan , Richter Clemens , Verhagen Dominique , VanEeden Arne , Horban Andrzej , Doroana Manuela , Antunes Francisco , Maltez Fernando , Sarmento-Castro Rui , Gonzalez Garcia Juan , Aldeguer José López , Clotet Bonaventura , Domingo Pere , Gatell Jose M , Knobel Hernando , Marquez Manuel , PilarMiralles Martin , Portilla Joaquin , Soriano Vicente , Tellez MariaJesus , Thalme Anders , Blaxhult Anders , Gisslen Magnus , Winston Alan , Fox Julie , Gompels Mark , Herieka Elbushra , Johnson Margaret , Leen Clifford , Pozniak Anton , Teague Alastair , Williams Ian , Boyd MarkAlastair , Grarup Jesper , Jansson Per O , Møller Nina Friis , MoseholmLarsen Ellen Frøsig , Morlat Philippe , Piroth Lionel , LeMoing Vincent , Wit Ferdinand W N M , Kowalska Justyna , Berenguer Juan , Moreno Santiago , Müller Nicolas J , Török Estée , Post Frank , Angus Brian , Calvez Vincent , Boucher Charles , Collins Simon , Dunn David , Lambert Sidonie , Marcelin Anne-Geneviève , Perno Carlo Federico , Pillay Deenan , White Ellen , Boffito Marta , Ammassari Adriana , Antinori Andrea , Stöhr Wolfgang , Autran Brigitte , Schmidt Reinhold Ernst , Odermarsky Michal , Smith Colette , Thiébaut Rodolphe , Arribas Jose , DeLaSerna Jose Ignacio Bernardino , Castagna Antonella , De Wit Stephane , Franquet Xavier , Furrer Hans-Jackob , Katlama Christine , Mocroft Amanda , Reiss Peter , Bucciardini Raffaella , Dedes Nikos , Fragola Vincenzo , George Elizabeth C , Lauriola Marco , Murri Rita , Nieuwkerk Pythia , Spire Bruno , Volny-Anne Alain , West Brian , Amieva Hélène , Antinori Andrea , Llibre Codina JosepMaria , Richert Laura , Stöhr Wolfgang , Winston Alan , Castelli Francesco , Braggion Marco , Focà Emanuele 
Published: November 2019

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&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].

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.