{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T15:35:33Z","timestamp":1787499333324,"version":"build-2736575974"},"reference-count":19,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T00:00:00Z","timestamp":1740700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Intramural Research projects","award":["ZIC ES103391-01"],"award-info":[{"award-number":["ZIC ES103391-01"]}]},{"name":"Division of Translational Toxicology"},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000016","name":"US Department of Health and Human Services","doi-asserted-by":"publisher","award":["HHSN273201400022C"],"award-info":[{"award-number":["HHSN273201400022C"]}],"id":[{"id":"10.13039\/100000016","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,5,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Abacavir (ABC), Dolutegravir (DTG), and Lamivudine (3TC) are part of a fixed-dose combination medication for the treatment of HIV. The three drugs offer different but complementary mechanisms of action by inhibiting reverse transcriptase and integrase, and ultimately inhibiting HIV replication. Due to the lack of information regarding long-term safety following in utero exposure, we are evaluating potential toxicity to offspring following in utero exposure to this combination therapy in Hsd:Sprague Dawley\u00aeSD\u00ae (HSD) rats, including cardiovascular toxicity and neurotoxicity. Generating internal exposure data are integral to putting toxicological findings into context. The objective of this work was to develop and validate a method to simultaneously quantitate ABC, DTG, and 3TC in rat matrices following exposure to this combination. The method used protein precipitation of plasma, fetal, placental, brain, or heart homogenate, followed by ultra-performance liquid chromatography-tandem mass spectrometry. In adult Sprague Dawley rat plasma, the method was linear (r\u2009\u2265\u20090.99) over the range 10\/15\/5 to 10,000\/15,000\/5000\u2009ng\/mL for ABC\/DTG\/3TC and recovery was \u226592% for all three analytes at all concentration levels. The limits of detection were 2.22, 3.69, and 0.978\u2009ng\/mL for ABC, DTG, and 3TC, respectively. Intra- and inter-day precision was \u22648.7% relative standard deviation (RSD), and relative error (RE) \u2264\u00b112.0% for standards prepared at 20\/30\/10, 400\/600\/200, and 5000\/7500\/2500\u2009ng\/mL. Matrix standards as high as 40\/60\/20\u2009\u00b5g\/mL could be diluted into the calibration range (RE\u2264\u00b13.5% and RSD \u22642.4%). The method was evaluated for HSD rat maternal plasma and fetal, placental, brain, and heart homogenates (mean RE \u2264\u00b115.0% and RSD \u22648.6%). Analyte stability was demonstrated in extracted plasma for 2 days at different temperatures, and in various matrices stored at \u221280\u00b0C for at least 32\u2009days (80\u2013113% of Day 0 concentrations). These data demonstrate that this simple and efficient method is suitable for quantitation of ABC, DTG, and 3TC in rat matrices generated from toxicology studies. The method can easily be adapted to other biological matrices and species (e.g. human).<\/jats:p>","DOI":"10.1093\/jat\/bkaf016","type":"journal-article","created":{"date-parts":[[2025,2,27]],"date-time":"2025-02-27T15:31:33Z","timestamp":1740670293000},"page":"332-339","source":"Crossref","is-referenced-by-count":2,"title":["HIV combination drug therapies: development and validation of an LC\u2013MS-MS method for simultaneous quantitation of abacavir, dolutegravir, and lamivudine in rat matrices in support of toxicology studies"],"prefix":"10.1093","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0234-3798","authenticated-orcid":false,"given":"Melanie A Rehder","family":"Silinski","sequence":"first","affiliation":[{"name":"RTI International , PO Box 12194, Research Triangle Park, NC 27709,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer A","family":"Gilliam","sequence":"additional","affiliation":[{"name":"RTI International , PO Box 12194, Research Triangle Park, NC 27709,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Apoian","sequence":"additional","affiliation":[{"name":"RTI International , PO Box 12194, Research Triangle Park, NC 27709,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda L","family":"Fletcher","sequence":"additional","affiliation":[{"name":"RTI International , PO Box 12194, Research Triangle Park, NC 27709,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9245-7790","authenticated-orcid":false,"given":"Reshan A","family":"Fernando","sequence":"additional","affiliation":[{"name":"RTI International , PO Box 12194, Research Triangle Park, NC 27709,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9512-090X","authenticated-orcid":false,"given":"Suramya","family":"Waidyanatha","sequence":"additional","affiliation":[{"name":"Division of Translational Toxicology, NIEHS , PO Box 12233, Research Triangle Park, NC 27709,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,2,28]]},"reference":[{"key":"2026032800161398100_R1","author":"Office of Environmental Health Hazard","year":"2011"},{"key":"2026032800161398100_R2","article-title":"Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors: Abacavir (Ziagen, ABC)","author":"U.S. Department of Health and Human Services."},{"key":"2026032800161398100_R3","author":"U.S. Department of Health and Human Services."},{"key":"2026032800161398100_R4","article-title":"Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors: Lamivudine (Epivir, 3TC)","author":"U.S. Department of Health and Human Services."},{"key":"2026032800161398100_R5","article-title":"Abacavir Sulfate and Lamivudine Tablets 60\/30 mg","author":"U.S. Food and Drug Administration.","year":"2012"},{"key":"2026032800161398100_R6","doi-asserted-by":"publisher","first-page":"1781","DOI":"10.1097\/QAD.0000000000001547","article-title":"Cardiovascular toxicity of abacavir: a clinical controversy in need of a pharmacological explanation","volume":"31","author":"Alvarez","year":"2017","journal-title":"Aids"},{"key":"2026032800161398100_R7","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1056\/NEJMoa1905230","article-title":"Neural-tube defects and antiretroviral treatment regimens in Botswana","volume":"381","author":"Zash","year":"2019","journal-title":"N Engl J Med"},{"key":"2026032800161398100_R8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/ofid\/ofaa482","article-title":"Randomized trial evaluating the neurotoxicity of dolutegravir\/abacavir\/lamivudine and its reversibility after switching to elvitegravir\/cobicistat\/emtricitabine\/tenofovir alafenamide: GESIDA 9016","volume":"7","author":"Valero","year":"2020","journal-title":"Open Forum Infect Dis"},{"key":"2026032800161398100_R9","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1016\/j.jchromb.2013.11.054","article-title":"A sensitive HPLC\u2013MS\/MS method for the determination of dolutegravir in human plasma","volume":"945\u20136","author":"Bennetto-Hood","year":"2014","journal-title":"J Chromatogr B Analyt Technol Biomed Life Sci"},{"key":"2026032800161398100_R10","first-page":"1081","article-title":"A sensitive LC-MS\/MS method for quantitative estimation of dolutegravir in human plasma","volume":"9","author":"Bodhankar","year":"2020","journal-title":"World J Pharm Res"},{"key":"2026032800161398100_R11","doi-asserted-by":"publisher","first-page":"18","DOI":"10.14205\/2309-4435.2015.03.01.3","article-title":"Comparative bioavailability study of two antiretroviral FDC containing abacavir 600mg and lamivudine 300mg in healthy human Indian volunteers","volume":"3","author":"Dan","year":"2015","journal-title":"J Appl Biopharm Pharmacokinet"},{"key":"2026032800161398100_R12","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2019.113057","article-title":"UPLC\u2013MS\/MS method for the simultaneous quantification of bictegravir and 13 others antiretroviral drugs plus cobicistat and ritonavir boosters in human plasma","volume":"181","author":"Gouget","year":"2020","journal-title":"J Pharm Biomedl Anal"},{"key":"2026032800161398100_R13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jchromb.2014.09.006","article-title":"A liquid chromatography\u2013tandem mass spectrometry assay for quantification of rilpivirine and dolutegravir in human plasma","volume":"971","author":"Gr\u00e9goire","year":"2014","journal-title":"J Chromatogr B Analyt Technol Biomed Life Sci"},{"key":"2026032800161398100_R14","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/j.jchromb.2016.05.040","article-title":"The development and application of a novel LC\u2013MS\/MS method for the measurement of dolutegravir, elvitegravir and cobicistat in human plasma","volume":"1027","author":"Penchala","year":"2016","journal-title":"J Chromatogr B Analyt Technol Biomed Life Sci"},{"key":"2026032800161398100_R15","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/j.jpba.2017.02.002","article-title":"UPLC\u2013MS\/MS method for the simultaneous quantification of three new antiretroviral drugs, dolutegravir, elvitegravir and rilpivirine, and other thirteen antiretroviral agents plus cobicistat and ritonavir boosters in human plasma","volume":"138","author":"Simiele","year":"2017","journal-title":"J Pharm Biomed Anal"},{"key":"2026032800161398100_R16","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1093\/chromsci\/48.8.654","article-title":"development and validation of a selective and rapid LC\u2013MS\u2013MS method for the quantification of abacavir in human plasma","volume":"48","author":"Yadav","year":"2010","journal-title":"J Chromatogr Sci"},{"key":"2026032800161398100_R17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2020.113119","article-title":"HPLC-MS\/MS method for the simultaneous quantification of dolutegravir, elvitegravir, rilpivirine, darunavir, ritonavir, raltegravir and raltegravir-\u03b2-d-glucuronide in human plasma","volume":"182","author":"Zheng","year":"2020","journal-title":"J Pharm Biomed Anal"},{"key":"2026032800161398100_R18","article-title":"Bioanalytical Method Validation: Guidance for Industry","author":"U.S. Food and Drug Administration.","year":"2018"},{"key":"2026032800161398100_R19","article-title":"Definition and Procedure for the Determination of the Method Detection Limit","author":"U.S. Environmental Protection Agency.","year":"2016"}],"container-title":["Journal of Analytical Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jat\/advance-article-pdf\/doi\/10.1093\/jat\/bkaf016\/62203921\/bkaf016.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jat\/article-pdf\/49\/5\/332\/62203921\/bkaf016.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jat\/article-pdf\/49\/5\/332\/62203921\/bkaf016.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T04:16:20Z","timestamp":1774671380000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jat\/article\/49\/5\/332\/8045954"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,28]]},"references-count":19,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,5,16]]}},"URL":"https:\/\/doi.org\/10.1093\/jat\/bkaf016","relation":{},"ISSN":["0146-4760","1945-2403"],"issn-type":[{"value":"0146-4760","type":"print"},{"value":"1945-2403","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,6]]},"published":{"date-parts":[[2025,2,28]]}}}