{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T04:43:41Z","timestamp":1768279421942,"version":"3.49.0"},"reference-count":34,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T00:00:00Z","timestamp":1744848000000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01AI091429"],"award-info":[{"award-number":["U01AI091429"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K08AI141740"],"award-info":[{"award-number":["K08AI141740"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Variability in the pharmacokinetics (PK) of first-line antituberculosis drugs (rifampicin [RIF], isoniazid [INH], and pyrazinamide [PZA]) is high and may be influenced by pharmacogenetic polymorphism. We performed a pharmacogenetic substudy in 90 participants with PK data from the HIRIF trial in Peru.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Relevant single-nucleotide polymorphisms (SNPs) in the NAT2, SLCO1B1, AADAC, and AOX1 loci were genotyped using real-time polymerase chain reaction (PCR).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The proportions of slow, intermediate, and fast acetylators predicted by a conventional 6-SNP NAT2 panel were 32.5%, 48.2%, and 19.2%, respectively. A single NAT2 tag SNP (rs1495741) agreed with the panel-predicted phenotype in 91% and was a better predictor of INH area under the curve (AUC). Accounting for discrepancies possibly caused by rare alleles not represented in the panel or that could be unequivocally resolved using observed AUC, sensitivity of the tag SNP was 97.7%. A previously described SNP in SLCO1B1 (rs4149032) was present at an allele frequency of 0.31 and appeared to influence RIF AUC and maximum concentration (Cmax) at a dose of 20\u2005mg\/kg, despite an extreme distribution of alleles across the randomized arms. The AADAC SNP (rs1803155) predominated in the study population and was not linked to RIF PK, although an effect could have been missed due to sample size and allele frequency. There was no association between PZA PK and a common SNP in AOX1 (rs55754655).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>A tag SNP approach may offer simpler and cheaper prediction of INH PK. Further exploration of the impact of SLCO1B1 SNPs on RIF PK is required in this and other populations.<\/jats:p>\n                  <jats:p>Clinical Trials Registration. NCT01408914.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/infdis\/jiaf195","type":"journal-article","created":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T00:01:38Z","timestamp":1744848098000},"source":"Crossref","is-referenced-by-count":1,"title":["Impact of Pharmacogenetics on Pharmacokinetics of First-Line Antituberculosis Drugs in the HIRIF Trial"],"prefix":"10.1093","author":[{"given":"Elizabeth","family":"Mackay","sequence":"first","affiliation":[{"name":"Department of Clinical Infection, Microbiology and immunology, University of Liverpool , Liverpool ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gareth","family":"Platt","sequence":"additional","affiliation":[{"name":"Department of Clinical Infection, Microbiology and immunology, University of Liverpool , Liverpool ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9002-7052","authenticated-orcid":false,"given":"Charles A","family":"Peloquin","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy and Translational Research, University of Florida , Gainesville, Florida ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meredith B","family":"Brooks","sequence":"additional","affiliation":[{"name":"Department of Global Health, Boston University School of Public Health , Boston, Massachusetts ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia M","family":"Coit","sequence":"additional","affiliation":[{"name":"Deparment of Global Health and Social Medicine, Harvard Medical School , Boston, Massachusetts ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1438-0692","authenticated-orcid":false,"given":"Gustavo E","family":"Vel\u00e1squez","sequence":"additional","affiliation":[{"name":"University of California Department of Medicine, , San Francisco, California ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henry","family":"Pertinez","sequence":"additional","affiliation":[{"name":"Department of Clinical Infection, Microbiology and immunology, University of Liverpool , Liverpool ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dante","family":"Vargas","sequence":"additional","affiliation":[{"name":"Department of Pneumonology, Hospital Nacional Hipolito Unanue , Lima ,","place":["Peru"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Epifanio","family":"S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Department of Pneumonology, Hospital Nacional Sergio Bernales , Lima ,","place":["Peru"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roger I","family":"Calder\u00f3n","sequence":"additional","affiliation":[{"name":"Advanced Research and Health , Lima ,","place":["Peru"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judith","family":"Jim\u00e9nez","sequence":"additional","affiliation":[{"name":"Socios en Salud , Lima ,","place":["Peru"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen","family":"Tintaya","sequence":"additional","affiliation":[{"name":"Socios en Salud , Lima ,","place":["Peru"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dalicxa","family":"Garcia","sequence":"additional","affiliation":[{"name":"Socios en Salud , Lima ,","place":["Peru"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elna","family":"Osso","sequence":"additional","affiliation":[{"name":"Deparment of Global Health and Social Medicine, Harvard Medical School , Boston, Massachusetts ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1363-3985","authenticated-orcid":false,"given":"Leo","family":"Lecca","sequence":"additional","affiliation":[{"name":"Deparment of Global Health and Social Medicine, Harvard Medical School , Boston, Massachusetts ,","place":["USA"]},{"name":"Socios en Salud , Lima ,","place":["Peru"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carole","family":"Mitnick","sequence":"additional","affiliation":[{"name":"Deparment of Global Health and Social Medicine, Harvard Medical School , Boston, Massachusetts ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3819-490X","authenticated-orcid":false,"given":"Geraint R","family":"Davies","sequence":"additional","affiliation":[{"name":"Department of Clinical Infection, Microbiology and immunology, University of Liverpool , Liverpool ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,4,17]]},"reference":[{"key":"2025050511022457900_jiaf195-B1","doi-asserted-by":"crossref","first-page":"e183","DOI":"10.1016\/S1473-3099(18)30110-5","article-title":"Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies","volume":"18","author":"Tiberi","year":"2018","journal-title":"Lancet Infect Dis"},{"key":"2025050511022457900_jiaf195-B2","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1007\/s40262-021-00997-0","article-title":"Population pharmacokinetics and Bayesian dose adjustment to advance TDM of anti-TB drugs","volume":"60","author":"Sturkenboom","year":"2021","journal-title":"Clin Pharmacokinet"},{"key":"2025050511022457900_jiaf195-B3","doi-asserted-by":"crossref","first-page":"2000955","DOI":"10.1183\/13993003.00955-2020","article-title":"PanACEA consortium. Increased bactericidal activity but dose-limiting intolerability at 50\u2005mg\u00b7kg-1 rifampicin","volume":"58","author":"Te Brake","year":"2021","journal-title":"Eur Respir J"},{"key":"2025050511022457900_jiaf195-B4","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/S1473-3099(16)30274-2","article-title":"PanACEA consortium.high-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial","volume":"17","author":"Boeree","year":"2017","journal-title":"Lancet Infect Dis"},{"key":"2025050511022457900_jiaf195-B5","doi-asserted-by":"crossref","first-page":"e220","DOI":"10.1016\/j.clinthera.2020.09.009","article-title":"A systematic review and meta-analysis of isoniazid pharmacokinetics in healthy volunteers and patients with tuberculosis","volume":"42","author":"Hong","year":"2020","journal-title":"Clin Ther"},{"key":"2025050511022457900_jiaf195-B6","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1007\/s00228-012-1429-9","article-title":"Pharmacogenetics-based tuberculosis therapy research group. NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: a randomized controlled trial for pharmacogenetics-based therapy","volume":"69","author":"Azuma","year":"2013","journal-title":"Eur J Clin Pharmacol"},{"key":"2025050511022457900_jiaf195-B7","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1097\/FPC.0000000000000423","article-title":"A pilot study to investigate the utility of NAT2 genotype-guided isoniazid monotherapy regimens in NAT2 slow acetylators","volume":"31","author":"Yoo","year":"2021","journal-title":"Pharmacogenet Genomics"},{"key":"2025050511022457900_jiaf195-B8","doi-asserted-by":"crossref","first-page":"2305","DOI":"10.1093\/jac\/dky152","article-title":"Pharmacokinetics of rifampicin in adult TB patients and healthy volunteers: a systematic review and meta-analysis","volume":"73","author":"Stott","year":"2018","journal-title":"J Antimicrob Chemother"},{"key":"2025050511022457900_jiaf195-B9","doi-asserted-by":"crossref","first-page":"4192","DOI":"10.1128\/AAC.00353-10","article-title":"Effects of tuberculosis, race, and human gene SLCO1B1 polymorphisms on rifampin concentrations","volume":"54","author":"Weiner","year":"2010","journal-title":"Antimicrob Agents Chemother"},{"key":"2025050511022457900_jiaf195-B10","doi-asserted-by":"crossref","first-page":"4122","DOI":"10.1128\/AAC.01833-10","article-title":"The SLCO1B1 rs4149032 polymorphism is highly prevalent in South Africans and is associated with reduced rifampin concentrations: dosing implications","volume":"55","author":"Chigutsa","year":"2011","journal-title":"Antimicrob Agents Chemother"},{"key":"2025050511022457900_jiaf195-B11","doi-asserted-by":"crossref","first-page":"987","DOI":"10.3855\/jidc.4696","article-title":"Low rifampicin concentrations in tuberculosis patients with HIV infection","volume":"8","author":"Gengiah","year":"2014","journal-title":"J Infect Dev Ctries"},{"key":"2025050511022457900_jiaf195-B12","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.5588\/ijtld.15.1007","article-title":"SLCO1B1 gene polymorphisms do not influence plasma rifampicin concentrations in a South Indian population","volume":"20","author":"Ramesh","year":"2016","journal-title":"Int J Tuberc Lung Dis"},{"key":"2025050511022457900_jiaf195-B13","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1128\/AAC.01195-15","article-title":"Effect of SLCO1B1 polymorphisms on rifabutin pharmacokinetics in African HIV-infected patients with tuberculosis","volume":"60","author":"Hennig","year":"2015","journal-title":"Antimicrob Agents Chemother"},{"key":"2025050511022457900_jiaf195-B14","doi-asserted-by":"crossref","first-page":"e00210-7","DOI":"10.1128\/AAC.00210-17","article-title":"Genetic determinants of the pharmacokinetic variability of rifampin in Malawian adults with pulmonary tuberculosis","volume":"61","author":"Sloan","year":"2017","journal-title":"Antimicrob Agents Chemother"},{"key":"2025050511022457900_jiaf195-B15","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1002\/cpt.1403","article-title":"The influence of pharmacogenetic variants in HIV\/tuberculosis coinfected patients in Uganda in the SOUTH study","volume":"106","author":"Calcagno","year":"2019","journal-title":"Clin Pharmacol Ther"},{"key":"2025050511022457900_jiaf195-B16","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1093\/trstmh\/trz108","article-title":"Role of pharmacogenetics in rifampicin pharmacokinetics and the potential effect on TB-rifampicin sensitivity among Ugandan patients","volume":"114","author":"Mukonzo","year":"2020","journal-title":"Trans R Soc Trop Med Hyg"},{"key":"2025050511022457900_jiaf195-B17","doi-asserted-by":"crossref","first-page":"e01964-18","DOI":"10.1128\/AAC.01964-18","article-title":"A population pharmacokinetic analysis shows that arylacetamide deacetylase (AADAC) gene polymorphism and HIV infection affect the exposure of rifapentine","volume":"63","author":"Francis","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"key":"2025050511022457900_jiaf195-B18","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1093\/jac\/dkaa490","article-title":"Pharmacokinetics\/pharmacodynamics group of tuberculosis trials consortium. Decreased plasma rifapentine concentrations associated with AADAC single nucleotide polymorphism in adults with tuberculosis","volume":"76","author":"Weiner","year":"2021","journal-title":"J Antimicrob Chemother"},{"key":"2025050511022457900_jiaf195-B19","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1164\/rccm.202309-1583OC","article-title":"A nanopore sequencing-based pharmacogenomic panel to personalize tuberculosis drug dosing","volume":"209","author":"Verma","year":"2024","journal-title":"Am J Crit Care Med"},{"key":"2025050511022457900_jiaf195-B20","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1007\/BF00558302","article-title":"Pharmacokinetics of pyrazinamide and its metabolites in healthy subjects","volume":"36","author":"Lacroix","year":"1989","journal-title":"Eur J Clin Pharmacol"},{"key":"2025050511022457900_jiaf195-B21","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1164\/rccm.201712-2524OC","article-title":"Efficacy and safety of high-dose rifampin in pulmonary tuberculosis. A randomized controlled trial","volume":"198","author":"Vel\u00e1squez","year":"2018","journal-title":"Am J Respir Crit Care Med"},{"key":"2025050511022457900_jiaf195-B22","doi-asserted-by":"crossref","first-page":"e00038-17","DOI":"10.1128\/AAC.00038-17","article-title":"Pharmacokinetic evidence from the HIRIF trial to support increased doses of rifampin for tuberculosis","volume":"61","author":"Peloquin","year":"2017","journal-title":"Antimicrob Agents Chemother"},{"key":"2025050511022457900_jiaf195-B23","doi-asserted-by":"crossref","first-page":"285","DOI":"10.2217\/pgs.13.230","article-title":"Full-gene sequencing analysis of NAT2 and its relationship with isoniazid pharmacokinetics in Venezuelan children with tuberculosis","volume":"15","author":"Verhagen","year":"2014","journal-title":"Pharmacogenomics"},{"key":"2025050511022457900_jiaf195-B24","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/tpj.2015.72","article-title":"NAT2 gene diversity and its evolutionary trajectory in the Americas","volume":"16","author":"Bisso-Machado","year":"2016","journal-title":"Pharmacogenomics J"},{"key":"2025050511022457900_jiaf195-B25","doi-asserted-by":"crossref","first-page":"e1764","DOI":"10.1002\/mgg3.1764","article-title":"Allelic and genotypic frequencies of NAT2, CYP2E1, and AADAC genes in a cohort of Peruvian tuberculosis patients","volume":"9","author":"Levano","year":"2021","journal-title":"Mol Genet Genomic Med"},{"key":"2025050511022457900_jiaf195-B26","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1097\/FPC.0b013e32833e1b54","article-title":"A single nucleotide polymorphism tags variation in the arylamine N-acetyltransferase 2 phenotype in populations of European background","volume":"21","author":"Garcia-Closas","year":"2011","journal-title":"Pharmacogenet Genomics"},{"key":"2025050511022457900_jiaf195-B27","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1097\/FPC.0000000000000224","article-title":"tagSNP rs1495741 as a useful molecular marker to predict antituberculosis drug-induced hepatotoxicity","volume":"26","author":"Chamorro","year":"2016","journal-title":"Pharmacogenet Genomics"},{"key":"2025050511022457900_jiaf195-B28","doi-asserted-by":"crossref","first-page":"293","DOI":"10.5588\/ijtld.18.0324","article-title":"NAT2 variants and toxicity related to anti-tuberculosis agents: a systematic review and meta-analysis","volume":"23","author":"Richardson","year":"2019","journal-title":"Int J Tuberc Lung Dis"},{"key":"2025050511022457900_jiaf195-B29","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1164\/rccm.202103-0564OC","article-title":"A rapid pharmacogenomic assay to detect NAT2 polymorphisms and guide isoniazid dosing for tuberculosis treatment","volume":"204","author":"Verma","year":"2021","journal-title":"Am J Crit Care Med"},{"key":"2025050511022457900_jiaf195-B30","doi-asserted-by":"crossref","first-page":"e00955-20","DOI":"10.1128\/AAC.00955-20","article-title":"Rifampicin transport by OATP1B1 variants","volume":"64","author":"Litjens","year":"2020","journal-title":"Antimicrob Agents Chemother"},{"key":"2025050511022457900_jiaf195-B31","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1053\/jhep.2002.34133","article-title":"Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver","volume":"36","author":"Vavricka","year":"2002","journal-title":"Hepatology"},{"key":"2025050511022457900_jiaf195-B32","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1007\/s11095-021-03107-8","article-title":"The effect of single nucleotide variations in the transmembrane domain of OATP1B1 on in vitro functionality","volume":"38","author":"Kiander","year":"2021","journal-title":"Pharm Res"},{"key":"2025050511022457900_jiaf195-B33","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1007\/s00228-007-0285-5","article-title":"Pharmacogenetics of SLCO1B1: haplotypes, htSNPs and hepatic expression in three distinct Asian populations","volume":"63","author":"Jada","year":"2007","journal-title":"Eur J Clin Pharm"},{"key":"2025050511022457900_jiaf195-B34","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1016\/j.bcp.2011.08.003","article-title":"Human arylacetamide deacetylase is responsible for deacetylation of rifamycins: rifampicin, rifabutin, and rifapentine","volume":"82","author":"Nakajima","year":"2011","journal-title":"Biochem Pharmacol"}],"container-title":["The Journal of Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jid\/advance-article-pdf\/doi\/10.1093\/infdis\/jiaf195\/62941261\/jiaf195.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/advance-article-pdf\/doi\/10.1093\/infdis\/jiaf195\/62941261\/jiaf195.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T15:02:53Z","timestamp":1746457373000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jid\/advance-article\/doi\/10.1093\/infdis\/jiaf195\/8114748"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,17]]},"references-count":34,"URL":"https:\/\/doi.org\/10.1093\/infdis\/jiaf195","relation":{},"ISSN":["0022-1899","1537-6613"],"issn-type":[{"value":"0022-1899","type":"print"},{"value":"1537-6613","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,17]]},"article-number":"jiaf195"}}