OBJECTIVE: Among HIV-positive patients prescribed ritonavir-boosted lopinavir, SLCO1B1 521T→C (rs4149056) is associated with increased plasma lopinavir exposure. Protease inhibitors (PIs) are also substrates for cytochrome P450 (CYP) 3A and ABCB1, which are induced by NR1I2. We characterized relationships between ABCB1, CYP3A4, CYP3A5, NR1I2, and SLCO1B1 polymorphisms and trough PI concentrations among AIDS Clinical Trials Group study A5146 participants. METHODS: At study entry, subjects with virologic failure on PI-containing regimens initiated new ritonavir-boosted PI regimens. We studied associations between week 2 PI plasma trough concentrations and 143 polymorphisms in these genes, including 4 targeted polymorphisms. RESULTS: Among 275 subjects with both drug concentrations andgenetic data, allelic frequencies of SLCO1B1 521T→C were 15%, 1%, and 8% in whites, blacks, and Hispanics, respectively. Further analyses were limited to 268 white, black, or Hispanic subjects who initiatedritonavir-boosted lopinavir (n = 98), fosamprenavir (n = 69), or saquinavir (n = 99). Of targeted polymorphisms, SLCO1B1 521T→C tended to be associated with higher lopinavir concentrations, with a 1.38-fold increase in the mean per C allele (95% confidence interval, 0.97-1.96; n = 98; P = 0.07). With fosamprenavir, SLCO1B1 521T→C was associated with lower amprenavir concentrations, with a 35% decrease in the mean per C allele (geometric mean ratio 0.65; 95% confidence interval, 0.44-0.94; n = 69; adjusted P = 0.02). There was no significant association with saquinavir concentrations, and none of the remaining 139 exploratory polymorphisms were statistically significant after correcting for multiple comparisons. CONCLUSIONS: With ritonavir-boosted PIs, a SLCO1B1 polymorphism that predicts higher lopinavir trough concentrations seems to predict lower amprenavir trough concentrations. The mechanism underlying this discordant association is uncertain.
RCT Entities:
OBJECTIVE: Among HIV-positivepatients prescribed ritonavir-boosted lopinavir, SLCO1B1 521T→C (rs4149056) is associated with increased plasma lopinavir exposure. Protease inhibitors (PIs) are also substrates for cytochrome P450 (CYP) 3A and ABCB1, which are induced by NR1I2. We characterized relationships between ABCB1, CYP3A4, CYP3A5, NR1I2, and SLCO1B1 polymorphisms and trough PI concentrations among AIDS Clinical Trials Group study A5146 participants. METHODS: At study entry, subjects with virologic failure on PI-containing regimens initiated new ritonavir-boosted PI regimens. We studied associations between week 2 PI plasma trough concentrations and 143 polymorphisms in these genes, including 4 targeted polymorphisms. RESULTS: Among 275 subjects with both drug concentrations and genetic data, allelic frequencies of SLCO1B1 521T→C were 15%, 1%, and 8% in whites, blacks, and Hispanics, respectively. Further analyses were limited to 268 white, black, or Hispanic subjects who initiated ritonavir-boosted lopinavir (n = 98), fosamprenavir (n = 69), or saquinavir (n = 99). Of targeted polymorphisms, SLCO1B1 521T→C tended to be associated with higher lopinavir concentrations, with a 1.38-fold increase in the mean per C allele (95% confidence interval, 0.97-1.96; n = 98; P = 0.07). With fosamprenavir, SLCO1B1 521T→C was associated with lower amprenavir concentrations, with a 35% decrease in the mean per C allele (geometric mean ratio 0.65; 95% confidence interval, 0.44-0.94; n = 69; adjusted P = 0.02). There was no significant association with saquinavir concentrations, and none of the remaining 139 exploratory polymorphisms were statistically significant after correcting for multiple comparisons. CONCLUSIONS: With ritonavir-boosted PIs, a SLCO1B1 polymorphism that predicts higher lopinavir trough concentrations seems to predict lower amprenavir trough concentrations. The mechanism underlying this discordant association is uncertain.
Authors: P Kuehl; J Zhang; Y Lin; J Lamba; M Assem; J Schuetz; P B Watkins; A Daly; S A Wrighton; S D Hall; P Maurel; M Relling; C Brimer; K Yasuda; R Venkataramanan; S Strom; K Thummel; M S Boguski; E Schuetz Journal: Nat Genet Date: 2001-04 Impact factor: 38.330
Authors: E Hustert; M Haberl; O Burk; R Wolbold; Y Q He; K Klein; A C Nuessler; P Neuhaus; J Klattig; R Eiselt; I Koch; A Zibat; J Brockmöller; J R Halpert; U M Zanger; L Wojnowski Journal: Pharmacogenetics Date: 2001-12
Authors: Gang Luo; Mark Cunningham; Sean Kim; Tim Burn; Jianrong Lin; Michael Sinz; Geraldine Hamilton; Christopher Rizzo; Summer Jolley; Darryl Gilbert; April Downey; Daniel Mudra; Richard Graham; Kathy Carroll; Jindong Xie; Ajay Madan; Andrew Parkinson; Dave Christ; Bernard Selling; Edward LeCluyse; Liang-Shang Gan Journal: Drug Metab Dispos Date: 2002-07 Impact factor: 3.922
Authors: S Hoffmeyer; O Burk; O von Richter; H P Arnold; J Brockmöller; A Johne; I Cascorbi; T Gerloff; I Roots; M Eichelbaum; U Brinkmann Journal: Proc Natl Acad Sci U S A Date: 2000-03-28 Impact factor: 11.205
Authors: Jose R Castillo-Mancilla; Christina L Aquilante; Michael F Wempe; Laura M Smeaton; Cynthia Firnhaber; Alberto M LaRosa; Nagalingeswaran Kumarasamy; Adriana Andrade; Gautam Baheti; Courtney V Fletcher; Thomas B Campbell; David W Haas; Samantha MaWhinney; Peter L Anderson Journal: J Antimicrob Chemother Date: 2016-02-17 Impact factor: 5.790
Authors: Daniel H Johnson; Charles Venuto; Marylyn D Ritchie; Gene D Morse; Eric S Daar; Paul J McLaren; David W Haas Journal: Pharmacogenet Genomics Date: 2014-04 Impact factor: 2.089
Authors: Leïla Belkhir; Laure Elens; Francis Zech; Nadtha Panin; Anne Vincent; Jean Cyr Yombi; Bernard Vandercam; Vincent Haufroid Journal: PLoS One Date: 2016-10-27 Impact factor: 3.240