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, L.; Gurjar, R.; Stohr, W.; Bonora, S.; Owen, A.; D'Avolio, A.; Cursley, A.; Molina, J. -M.; Faetkenheuer, G.; Vandekerckhove, L.; 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, A. G.; Pillay, D.; Franquet, X.; Schwarze, S.; Grarup, J.; Fischer, A.; Wallet, C.; Diallo, A.; Saillard, J.; Moecklinghoff, C.; Stellbrink, H. -J.; Vanleeuwen, R.; Gatell, J.; Sandstrom, E.; Flepp, M.; Ewings, F.; George, E. C.; Hudson, F.; Pearce, G.; Quercia, R.; Rogatto, F.; Leavitt, R.; Nguyen, B. -Y.; 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, A.; 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, M. -L.; Jansson, P. O.; Jensen, K.; Mariajoensen, Z.; Moseholmlarsen, E.; Pahl, C.; Pearson, M.; Nielsen, B. R.; Reilev, So. S.; Christ, I.; Lathouwers, D.; Manting, C.; Van Leeuwen, R.; Mendy, B.; Metro, A.; Couffin-Cadiergues, S.; Knellwolf, A. -L.; Palmisiano, L.; Aznar, E.; Barea, C.; Cotarelo, M.; Esteban, H.; Girbau, I.; Moyano, B.; Ramirez, M.; Saiz, C.; Sanchez, I.; Yllescas, M.; Binelli, A.; Colasanti, V.; Massella, M.; Anagnostou, O.; Gioukari, V.; Touloumi, G.; Schmied, B.; Rieger, A.; Vetter, N.; Dewit, S.; Florence, E.; Gerstoft, J.; Mathiesen, L.; Katlama, C.; Cabie, A.; Cheret, A.; Dupon, M.; Ghosn, J.; Girard, P. -M.; Goujard, C.; Levy, Y.; Morlat, P.; Neau, D.; Obadia, M.; Perre, P.; Piroth, L.; Reynes, J.; Tattevin, P.; Ragnaud, J. M.; Weiss, L.; Yazdan, Y.; Yeni, P.; Zucman, D.; Esser, S.; Fatkenheuer, G.; Hoffmann, C.; Jessen, H.; Rockstroh, J.; Schmidt, R.; Stephan, C.; Unger, S.; Hatzakis, A.; Daikos, G. L.; Papadopoulos, A.; Skoutelis, A.; Banhegyi, D.; Mallon, P.; Mulcahy, F.; Andreoni, M.; Castelli, F.; D'Arminiomonforte, A.; Diperri, G.; Galli, M.; Lazzarin, A.; Mazzotta, F.; Torti, C.; Vullo, V.; Prins, J.; Richter, C.; Verhagen, D.; Vaneeden, A.; Doroana, M.; Antunes, F.; Maltez, F.; Sarmento-Castro, R.; Gonzalez Garcia, J.; Aldeguer, J. L.; Clotet, B.; Domingo, P.; Gatell, J. M.; Knobel, H.; Marquez, M.; Pilarmiralles, M.; Portilla, J.; Soriano, V.; Tellez, M.; Thalme, A.; Blaxhult, A.; Gisslen, M.; Winston, A.; Fox, J.; Gompels, M.; Herieka, E.; Johnson, M.; Leen, C.; Teague, A.; Williams, I.; Boyd, M.; Moller, N. F.; Moseholmlarsen, E. F.; Lemoing, V.; Wit, F. W. N. M.; Kowalska, J.; Berenguer, J.; Moreno, S.; Muller, N. J.; Torok, E.; Post, F.; Angus, B.; Calvez, V.; Boucher, C.; Collins, S.; Dunn, D.; Lambert, S.; Marcelin, A. -G.; Perno, C. F.; White, E.; Ammassari, A.; Schmidt, R. E.; Odermarsky, M.; Smith, C.; Thiebaut, R.; Delaserna, J. I. B.; Castagna, A.; De Wit, S.; Furrer, H. -J.; Mocroft, A.; Reiss, P.; Fragola, V.; Lauriola, M.; Murri, R.; Nieuwkerk, P.; Spire, B.; Volny-Anne, A.; West, B.; Amieva, H.; Llibre Codina, J.; Braggion, M.; Foca, E.

doi:10.1093/jac/dkz479

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.