{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T04:43:02Z","timestamp":1791434582981,"version":"4.3.3"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2022,2,4]],"date-time":"2022-02-04T00:00:00Z","timestamp":1643932800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UM1AI068632"],"award-info":[{"award-number":["UM1AI068632"]}],"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":["UM1AI068616"],"award-info":[{"award-number":["UM1AI068616"]}],"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":["UM1AI106716"],"award-info":[{"award-number":["UM1AI106716"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["HHSN275201800001I"],"award-info":[{"award-number":["HHSN275201800001I"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,9,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Isoniazid (INH) metabolism depends on the N-acetyl transferase 2 (NAT2) enzyme, whose maturation process remains unknown in low birth weight (LBW) and preterm infants. We aimed to assess INH exposure and safety in infants receiving oral tuberculosis prevention.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>This population pharmacokinetics (PK) analysis used INH and N-acetyl-isoniazid (ACL) concentrations in infants (BW \u2264 4\u00a0kg), including preterm, with follow-up for 6 months. PK parameters were described using nonlinear mixed effects modeling. Simulations were performed to assess INH exposure and optimal dosing regimens, using 2 targets: Cmax at 3\u20136\u00a0mg\/L and area under the curve (AUC) \u2265 10.52\u00a0mg h\/L.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We included 57 infants (79% preterm, 84% LBW) in the PK analysis, with a median (range) gestational age of 34 (28.7\u201339.4) weeks. At the time of sampling, postnatal age was 2.3 (0.2\u20137.3) months and weight (WT) was 3.7 (0.9\u20139.3) kg. NAT2 genotype was available in 43 (75.4%) patients (10 slow, 26 intermediate, and 7 fast metabolizers). Ninety percent of NAT2 maturation was attained by 4.4 post-natal months. WT, postmenstrual age, and NAT2 genotype significantly influenced INH exposure, with a 5-fold difference in AUC between slow and fast metabolizers for the same dose. INH appeared safe across the broad range of exposure for 61 infants included in the safety analysis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>In LBW\/preterm infants, INH dosing needs frequent adjustment to account for growth and maturation. Pharmacogenetics-based dosing regimens is the most powerful approach to deliver safe and equalized exposures for all infants, because NAT2 genotype highly impacts INH pharmacokinetic variability.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cid\/ciac001","type":"journal-article","created":{"date-parts":[[2022,2,2]],"date-time":"2022-02-02T04:12:19Z","timestamp":1643775139000},"page":"1037-1045","source":"Crossref","is-referenced-by-count":12,"title":["Influence of NAT2 Genotype and Maturation on Isoniazid Exposure in Low-Birth-Weight and Preterm Infants With or Without Human Immunodeficiency Virus (HIV) Exposure"],"prefix":"10.1093","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9751-8249","authenticated-orcid":false,"given":"Agathe","family":"B\u00e9ranger","sequence":"first","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences, University of California San Francisco , San Francisco, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrie","family":"Bekker","sequence":"additional","affiliation":[{"name":"Family Center for Research with Ubuntu, Department of Paediatrics and Child Health, Stellenbosch University and Tygerberg Hospital , Cape Town , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bel\u00e9n P","family":"Solans","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences, University of California San Francisco , San Francisco, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark F","family":"Cotton","sequence":"additional","affiliation":[{"name":"Family Center for Research with Ubuntu, Department of Paediatrics and Child Health, Stellenbosch University and Tygerberg Hospital , Cape Town , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Mirochnick","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, Boston University School of Medicine , Boston, Massachusetts , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avy","family":"Violari","sequence":"additional","affiliation":[{"name":"Perinatal HIV Research Unit, University of the Witwatersrand , Johannesburg , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajia","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Heath , Boston, Massachusetts , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mae","family":"Cababasay","sequence":"additional","affiliation":[{"name":"Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Heath , Boston, Massachusetts , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lubbe","family":"Wiesner","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Cape Town , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renee","family":"Browning","sequence":"additional","affiliation":[{"name":"Division of AIDS, National Institute of Allergy and Infectious Diseases, NIH , Bethesda, Maryland , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Moye","sequence":"additional","affiliation":[{"name":"Division of Extramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, Maryland , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edmund V","family":"Capparelli","sequence":"additional","affiliation":[{"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego , La Jolla, California , USA"},{"name":"Pediatrics Department, Rady Children\u2019s Hospital San Diego, University of California San Diego , La Jolla, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radojka M","family":"Savic","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences, University of California San Francisco , San Francisco, California , USA"},{"name":"UCSF Center for Tuberculosis, University of California San Francisco , San Francisco, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,2,4]]},"reference":[{"key":"2022092921011112400_CIT0001","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/S0140-6736(20)30166-5","article-title":"The risk of 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