Influence of UGT1A1 and SLC22A6 polymorphisms on the population pharmacokinetics and pharmacodynamics of raltegravir in HIV-infected adults: a NEAT001/ANRS143 sub-study.
Journal
The pharmacogenomics journal
ISSN: 1473-1150
Titre abrégé: Pharmacogenomics J
Pays: United States
ID NLM: 101083949
Informations de publication
Date de publication:
01 2023
01 2023
Historique:
received:
08
12
2021
accepted:
29
09
2022
revised:
13
09
2022
pubmed:
21
10
2022
medline:
16
2
2023
entrez:
20
10
2022
Statut:
ppublish
Résumé
Using concentration-time data from the NEAT001/ARNS143 study (single sample at week 4 and 24), we determined raltegravir pharmacokinetic parameters using nonlinear mixed effects modelling (NONMEM v.7.3; 602 samples from 349 patients) and investigated the influence of demographics and SNPs (SLC22A6 and UGT1A1) on raltegravir pharmacokinetics and pharmacodynamics. Demographics and SNPs did not influence raltegravir pharmacokinetics and no significant pharmacokinetic/pharmacodynamic relationships were observed. At week 96, UGT1A1*28/*28 was associated with lower virological failure (p = 0.012), even after adjusting for baseline CD4 count (p = 0.048), but not when adjusted for baseline HIV-1 viral load (p = 0.082) or both (p = 0.089). This is the first study to our knowledge to assess the influence of SNPs on raltegravir pharmacodynamics. The lack of a pharmacokinetic/pharmacodynamic relationship is potentially an artefact of raltegravir's characteristic high inter and intra-patient variability and also suggesting single time point sampling schedules are inadequate to thoroughly assess the influence of SNPs on raltegravir pharmacokinetics.
Identifiants
pubmed: 36266537
doi: 10.1038/s41397-022-00293-5
pii: 10.1038/s41397-022-00293-5
pmc: PMC9584256
doi:
Substances chimiques
Raltegravir Potassium
43Y000U234
Anti-HIV Agents
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
14-20Subventions
Organisme : Medical Research Council
ID : MC_UU_00004/03
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
Références
Steigbigel RT, Cooper DA, Teppler H, Eron JJ, Gatell JM, Kumar PN, et al. Long‐term efficacy and safety of raltegravir combined with optimized background therapy in treatment‐experienced patients with drug‐resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 phase III trials. Clin Infect Dis. 2010;50:605–12.
pubmed: 20085491
doi: 10.1086/650002
Rockstroh JK, Lennox JL, DeJesus E, Saag MS, Lazzarin A, Wan H, et al. Long-term treatment with raltegravir or efavirenz combined with tenofovir/emtricitabine for treatment-naive human immunodeficiency virus-1–infected patients: 156-week results from STARTMRK. Clin Infect Dis. 2011;53:807–16.
pubmed: 21921224
doi: 10.1093/cid/cir510
Ryom L, Cotter A, De Miguel R, Béguelin C, Podlekareva D, Arribas JR, et al. 2019 update of the European AIDS Clinical Society Guidelines for treatment of people living with HIV version 10.0. HIV Med. 2020;21:617–24.
pubmed: 32885559
pmcid: 7754379
doi: 10.1111/hiv.12878
DHHS. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. 2021; 40. https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf .
Cahn P, Sax PE, Squires K, Molina J-M, Ratanasuwan W, Rassool M, et al. Raltegravir 1200 mg once daily vs 400 mg twice daily, with emtricitabine and tenofovir disoproxil fumarate, for previously untreated HIV-1 infection: week 96 results from ONCEMRK, a randomized, double-blind, noninferiority trial. J Acquir Immune Defic Syndr. 2018;78:589–98.
pubmed: 29771789
pmcid: 6075877
doi: 10.1097/QAI.0000000000001723
Kassahun K, McIntosh I, Cui D, Hreniuk D, Merschman S, Lasseter K, et al. Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency virus 1 integrase enzyme. Drug Metab Dispos. 2007;35:1657–63.
pubmed: 17591678
doi: 10.1124/dmd.107.016196
Anker M, Corales RB. Raltegravir (MK-0518): a novel integrase inhibitor for the treatment of HIV infection. Expert Opin Investig Drugs. 2008;17:97–103.
pubmed: 18095922
doi: 10.1517/13543784.17.1.97
Burger DM. Drug-drug interactions with raltegravir. Eur J Med Res. 2009;14:17–21.
pubmed: 19959412
pmcid: 3516822
Burger DM. Raltegravir: a review of its pharmacokinetics, pharmacology and clinical studies. Expert Opin Drug Metab Toxicol. 2010;6:1151–60.
pubmed: 20701552
doi: 10.1517/17425255.2010.513383
Siccardi M, DʼAvolio A, Rodriguez-Novoa S, Cuenca L, Simiele M, Baietto L, et al. Intrapatient and interpatient pharmacokinetic variability of raltegravir in the clinical setting. Ther Drug Monit. 2012;34:232–5.
pubmed: 22406652
doi: 10.1097/FTD.0b013e31824aa50a
Messiaen P, Wensing AMJ, Fun A, Nijhuis M, Brusselaers N, Vandekerckhove L. Clinical use of HIV integrase inhibitors: a systematic review and meta-analysis. PLoS One. 2013;8:e52562.
pubmed: 23341902
pmcid: 3541389
doi: 10.1371/journal.pone.0052562
Elliot E, Chirwa M, Boffito M. How recent findings on the pharmacokinetics and pharmacodynamics of integrase inhibitors can inform clinical use. Curr Opin Infect Dis. 2017;30:58–73.
pubmed: 27798496
doi: 10.1097/QCO.0000000000000327
Belkhir L, Seguin-Devaux C, Elens L, Pauly C, Gengler N, Schneider S, et al. Impact of UGT1A1 polymorphisms on Raltegravir and its glucuronide plasma concentrations in a cohort of HIV-1 infected patients. Sci Rep. 2018;8:7359.
pubmed: 29743555
pmcid: 5943329
doi: 10.1038/s41598-018-25803-z
Wenning L, Petry A, Kost J, Jin B, Breidinger S, DeLepeleire I, et al. Pharmacokinetics of raltegravir in individuals with UGT1A1 polymorphisms. Clin Pharm Ther. 2009;85:623–7.
doi: 10.1038/clpt.2009.12
Yagura H, Watanabe D, Ashida M, Kushida H, Hirota K, Ikuma M, et al. Correlation between UGT1A1 polymorphisms and raltegravir plasma trough concentrations in Japanese HIV-1-infected patients. J Infect Chemother. 2015;21:713–7.
pubmed: 26233886
doi: 10.1016/j.jiac.2015.06.008
Hirano A, Ikemura K, Takahashi M, Shibata M, Amioka K, Nomura T, et al. Lack of correlation between UGT1A1 *6, *28 genotypes, and plasma raltegravir concentrations in Japanese HIV type 1-infected patients. AIDS Res Hum Retroviruses. 2012;28:776–9.
pubmed: 21978357
doi: 10.1089/aid.2011.0231
Neely M, Decosterd L, Fayet A, Lee JSF, Margol A, Kanani M, et al. Pharmacokinetics and pharmacogenomics of once-daily raltegravir and atazanavir in healthy volunteers. Antimicrob Agents Chemother. 2010;54:4619–25.
pubmed: 20823282
pmcid: 2976128
doi: 10.1128/AAC.00712-10
Moss DM, Kwan WS, Liptrott NJ, Smith DL, Siccardi M, Khoo SH, et al. Raltegravir is a substrate for SLC22A6: a putative mechanism for the interaction between raltegravir and tenofovir. Antimicrob Agents Chemother. 2011;55:879–87.
pubmed: 21078936
doi: 10.1128/AAC.00623-10
Moss DM, Neary M, Owen A. The role of drug transporters in the kidney: lessons from tenofovir. Front Pharm. 2014;5:1–14.
doi: 10.3389/fphar.2014.00248
Raffi F, Babiker AG, Richert L, Molina J-M, George EC, Antinori A, et al. Ritonavir-boosted darunavir combined with raltegravir or tenofovir–emtricitabine in antiretroviral-naive adults infected with HIV-1: 96 week results from the NEAT001/ANRS143 randomised non-inferiority trial. Lancet. 2014;384:1942–51.
pubmed: 25103176
doi: 10.1016/S0140-6736(14)61170-3
Chen S, St Jean P, Borland J, Song I, Yeo AJ, Piscitelli S, et al. Evaluation of the effect of UGT1A1 polymorphisms on dolutegravir pharmacokinetics. Pharmacogenomics. 2014;15:9–16.
pubmed: 24329186
doi: 10.2217/pgs.13.190
Arab-Alameddine M, Fayet-Mello A, Lubomirov R, Neely M, di Iulio J, Owen A, et al. Population pharmacokinetic analysis and pharmacogenetics of raltegravir in HIV-positive and healthy individuals. Antimicrob Agents Chemother. 2012;56:2959–66.
pubmed: 22371894
pmcid: 3370715
doi: 10.1128/AAC.05424-11
Wang L, Soon GH, Seng K-Y, Li J, Lee E, Yong E-L, et al. Pharmacokinetic modeling of plasma and intracellular concentrations of raltegravir in healthy volunteers. Antimicrob Agents Chemother. 2011;55:4090–5.
pubmed: 21746959
pmcid: 3165315
doi: 10.1128/AAC.00593-11
Rizk ML, Hang Y, Luo W-L, Su J, Zhao J, Campbell H, et al. Pharmacokinetics and pharmacodynamics of once-daily versus twice-daily raltegravir in treatment-naïve HIV-infected patients. Antimicrob Agents Chemother. 2012;56:3101–6.
pubmed: 22430964
pmcid: 3370742
doi: 10.1128/AAC.06417-11
Iwamoto M, Wenning LA, Petry AS, Laethem M, De Smet M, Kost JT, et al. Minimal effects of ritonavir and efavirenz on the pharmacokinetics of raltegravir. Antimicrob Agents Chemother. 2008;52:4338–43.
pubmed: 18838589
pmcid: 2592871
doi: 10.1128/AAC.01543-07
Vera JH, Jackson A, Dickinson L, Else L, Barber T, Mora-Peris B, et al. The pharmacokinetic profile of raltegravir-containing antiretroviral therapy in HIV-infected individuals over 60 years of age. HIV Clin Trials. 2015;16:39–42.
pubmed: 25777188
doi: 10.1179/1528433614Z.0000000006
Nicolas J-M, Espie P, Molimard M. Gender and interindividual variability in pharmacokinetics. Drug Metab Rev. 2009;41:408–21.
pubmed: 19601720
doi: 10.1080/10837450902891485
Johnson JA. Predictability of the effects of race or ethnicity on pharmacokinetics of drugs. Int J Clin Pharm Ther. 2000;38:53–60.
doi: 10.5414/CPP38053
Mangoni AA, Jackson SHD. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. Br J Clin Pharm. 2003;57:6–14.
doi: 10.1046/j.1365-2125.2003.02007.x
Brainard DM, Wenning LA, Stone JA, Wagner JA, Iwamoto M. Clinical pharmacology profile of raltegravir, an HIV-1 integrase strand transfer inhibitor. J Clin Pharm. 2011;51:1376–402.
doi: 10.1177/0091270010387428
Nettles RE, Kieffer TL, Parsons T, Johnson J, Cofrancesco J, Gallant JE, et al. Marked intraindividual variability in antiretroviral concentrations may limit the utility of therapeutic drug monitoring. Clin Infect Dis. 2006;42:1189–96.
pubmed: 16575741
doi: 10.1086/501458
Elzi L, Erb S, Furrer H, Cavassini M, Calmy A, Vernazza P, et al. Adverse events of raltegravir and dolutegravir. AIDS. 2017;31:1853–8.
pubmed: 28692533
doi: 10.1097/QAD.0000000000001590
Yagura H, Watanabe D, Kushida H, Tomishima K, Togami H, Hirano A, et al. Impact of UGT1A1 gene polymorphisms on plasma dolutegravir trough concentrations and neuropsychiatric adverse events in Japanese individuals infected with HIV-1. BMC Infect Dis. 2017;17:622.
pubmed: 28915895
pmcid: 5603066
doi: 10.1186/s12879-017-2717-x
Takano M, Sugiyama T. UGT1A1 polymorphisms in cancer: impact on irinotecan treatment. Pharmgenom Pers Med. 2017;10:61–68.
Krishna R, Rizk ML, Larson P, Schulz V, Kesisoglou F, Pop R. Single- and multiple-dose pharmacokinetics of once-daily formulations of raltegravir. Clin Pharm Drug Dev. 2018;7:196–206.
doi: 10.1002/cpdd.358
Cahn P, Kaplan R, Sax PE, Squires K, Molina J-M, Avihingsanon A, et al. Raltegravir 1200 mg once daily versus raltegravir 400 mg twice daily, with tenofovir disoproxil fumarate and emtricitabine, for previously untreated HIV-1 infection: a randomised, double-blind, parallel-group, phase 3, non-inferiority trial. Lancet HIV. 2017;4:e486–e494.
pubmed: 28918877
doi: 10.1016/S2352-3018(17)30128-5
Brainard DM, Friedman EJ, Jin B, Breidinger SA, Tillan MD, Wenning LA, et al. Effect of low-, moderate-, and high-fat meals on raltegravir pharmacokinetics. J Clin Pharm. 2011;51:422–7.
doi: 10.1177/0091270010367652
Ette EI, Kelman AW, Howie CA, Whiting B. Analysis of animal pharmacokinetic data: performance of the one point per animal design. J Pharmacokinet Biopharm. 1995;23:551–66.
pubmed: 8733946
doi: 10.1007/BF02353461
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. J Antimicrob Chemother. 2020;75:628–39.
pubmed: 31754703
doi: 10.1093/jac/dkz479
D’Avolio A, Baietto L, Siccardi M, Sciandra M, Simiele M, Oddone V, et al. An HPLC-PDA method for the simultaneous quantification of the HIV integrase inhibitor raltegravir, the new nonnucleoside reverse transcriptase inhibitor etravirine, and 11 other antiretroviral agents in the plasma of HIV-infected patients. Ther Drug Monit. 2008;30:662–9.
pubmed: 18824956
doi: 10.1097/FTD.0b013e318189596d
Olagunju A, Bolaji O, Amara A, Else L, Okafor O, Adejuyigbe E, et al. Pharmacogenetics of pregnancy-induced changes in efavirenz pharmacokinetics. Clin Pharm Ther. 2015;97:298–306.
doi: 10.1002/cpt.43
Lee LS-U, Seng K-Y, Wang L-Z, Yong W-P, Hee K-H, Soh TI, et al. Phenotyping of UGT1A1 activity using raltegravir predicts pharmacokinetics and toxicity of irinotecan in FOLFIRI. PLoS One. 2016;11:e0147681.
pubmed: 26808671
pmcid: 4726617
doi: 10.1371/journal.pone.0147681
Beal SL, Sheiner L. NONMEM users guide. ICON Dev Soluntions, Ellicott City, Maryland, USA.
Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med. 1995;333:1171–5.
pubmed: 7565971
doi: 10.1056/NEJM199511023331802
Hsieh T-Y, Shiu T-Y, Huang S-M, Lin H-H, Lee T-C, Chen P-J, et al. Molecular pathogenesis of Gilbert’s syndrome: decreased TATA-binding protein binding affinity of UGT1A1 gene promoter. Pharmacogenet Genom. 2007;17:229–36.
doi: 10.1097/FPC.0b013e328012d0da
Gammal R, Court M, Haidar C, Iwuchukwu O, Gaur A, Alvarellos M, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for UGT1A1 and atazanavir prescribing. Clin Pharm Ther. 2016;99:363–9.
doi: 10.1002/cpt.269
Dickinson L, Amin J, Else L, Boffito M, Egan D, Owen A, et al. Comprehensive pharmacokinetic, pharmacodynamic and pharmacogenetic evaluation of once-daily Efavirenz 400 and 600 mg in treatment-naïve HIV-infected patients at 96 weeks: results of the ENCORE1 study. Clin Pharmacokinet. 2016;55:861–73.
pubmed: 26715213
doi: 10.1007/s40262-015-0360-5
Lindbom L, Pihlgren P, Jonsson N. PsN-Toolkit—a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Prog Biomed. 2005;79:241–57.
doi: 10.1016/j.cmpb.2005.04.005
Jonsson EN, Karlsson MO. Xpose—an S-PLUS-based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Prog Biomed. 1998;58:51–64.
doi: 10.1016/S0169-2607(98)00067-4
White IR, Royston P. Imputing missing covariate values for the Cox model. Stat Med. 2009;28:1982–98.
pubmed: 19452569
pmcid: 2998703
doi: 10.1002/sim.3618
Lambert-Niclot S, George EC, Pozniak A, White E, Schwimmer C, Jessen H, et al. Antiretroviral resistance at virological failure in the NEAT 001/ANRS 143 trial: Raltegravir plus darunavir/ritonavir or tenofovir/emtricitabine plus darunavir/ritonavir as first-line ART. J Antimicrob Chemother. 2016;71:1056–62.
pubmed: 26702926
doi: 10.1093/jac/dkv427
Wensing AM, Calvez V, Ceccherini-Silberstein F, Charpentier C, Günthard HF, Paredes R, et al. 2014 Update of the drug resistance mutations in HIV-1. Top Antivir Med. 2017;27:111–21.