{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T10:25:38Z","timestamp":1767867938710,"version":"3.49.0"},"reference-count":25,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T00:00:00Z","timestamp":1613606400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Therapeutic drug monitoring (TDM) is used in certain clinically selected cases and in research settings to optimize the response to antiretroviral therapy. Plasma of blood is commonly used for TDM, but blood sampling is invasive and at risk for transmission of infectious agents. On the other hand, saliva sampling is noninvasive, safe, cheap, and easily performed compared to blood. Dolutegravir (DTG) is now widely prescribed as a key component of antiretroviral therapy for HIV infection. In this study, we examined the relationship between DTG concentrations in plasma and saliva of treated patients to explore the possibility of using saliva as an alternative body fluid of TDM. A total of 17 pairs of blood and saliva samples were obtained from 15 consented HIV-1-infected subjects treated with DTG containing regimens for more than one month. Both blood and saliva samples were collected within 1 h of each other. Drug concentrations were determined by liquid chromatography-tandem mass spectrometry using DTG-d5 as an internal standard. The LLOQ was 0.5 ng\/mL. The calibration curves were prepared with pooled plasma or saliva containing DTG in a range of 0.5\u2013100 ng\/mL with precision of &lt;14.4% and accuracy within \u00b114.7%. The DTG concentrations in the plasma and saliva were significantly correlated (Pearson\u2019s correlation coefficient <jats:italic>r<\/jats:italic> = 0.76, <jats:italic>p<\/jats:italic> &lt; 0.001). The median ratio of the drug concentration in saliva to those in plasma was 0.0056, which is close to the rate of non-protein-bound DTG in plasma (0.70%), suggesting that only free DTG in plasma is transported to the salivary glands and secreted into saliva. The present study demonstrates that DTG concentration in saliva reflects the pharmacologically active drug concentration in plasma and may provide an easily accessible alternative for monitoring effective antiretroviral treatment.<\/jats:p>","DOI":"10.1371\/journal.pone.0246994","type":"journal-article","created":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T19:06:08Z","timestamp":1613675168000},"page":"e0246994","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Saliva as a potential matrix for evaluating pharmacologically active dolutegravir concentration in plasma"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9899-8726","authenticated-orcid":true,"given":"Eiko","family":"Yamada","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ritsuo","family":"Takagi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4588-5845","authenticated-orcid":true,"given":"Hiroshi","family":"Moro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koji","family":"Sudo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8125-1981","authenticated-orcid":true,"given":"Shingo","family":"Kato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,2,18]]},"reference":[{"key":"pone.0246994.ref001","doi-asserted-by":"crossref","first-page":"741","DOI":"10.2165\/00003495-200363080-00002","article-title":"Therapeutic drug monitoring: an aid to optimising response to antiretroviral drugs?","volume":"63","author":"RE Aarnoutse","year":"2003","journal-title":"Drugs"},{"key":"pone.0246994.ref002","doi-asserted-by":"crossref","first-page":"211","DOI":"10.2165\/00003088-199630030-00003","article-title":"Drug monitoring in nonconventional biological fluids and matrices","volume":"30","author":"S Pichini","year":"1996","journal-title":"Clin Pharmacokinet"},{"key":"pone.0246994.ref003","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1097\/FTD.0b013e31819f3328","article-title":"Pharmacokinetics and therapeutic drug monitoring of psychotropic drugs in pediatrics","volume":"31","author":"S Pichini","year":"2009","journal-title":"Ther Drug Monit"},{"key":"pone.0246994.ref004","doi-asserted-by":"crossref","first-page":"567","DOI":"10.5414\/CP202789","article-title":"Plasma and saliva concentrations of abacavir, tenofovir, darunavir, and raltegravir in HIV-1-infected patients","volume":"55","author":"E Yamada","year":"2017","journal-title":"Int J Clin Pharmacol Ther"},{"key":"pone.0246994.ref005","doi-asserted-by":"crossref","first-page":"3547","DOI":"10.2147\/DDDT.S84850","article-title":"Dolutegravir\u2014a review of the pharmacology, efficacy, and safety in the treatment of HIV","volume":"9","author":"CE Kandel","year":"2015","journal-title":"Drug Des Devel Ther"},{"key":"pone.0246994.ref006","doi-asserted-by":"crossref","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\u2013946","author":"C Bennetto-Hood","year":"2014","journal-title":"J Chromatogr B"},{"key":"pone.0246994.ref007","doi-asserted-by":"crossref","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":"M Simiele","year":"2017","journal-title":"J Pharm Biomed Anal"},{"key":"pone.0246994.ref008","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.jchromb.2018.12.008","article-title":"Development and validation of an UPLC-MS\/MS bioanalytical method for simultaneous quantification of the antiretroviral drugs dolutegravir, elvitegravir, raltegravir, nevirapine and etravirine in human plasma","volume":"1105","author":"PDJ Bollen","year":"2019","journal-title":"J Chromatogr B"},{"key":"pone.0246994.ref009","doi-asserted-by":"crossref","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":"Y Zheng","year":"2020","journal-title":"J Pharm Biomed Anal"},{"key":"pone.0246994.ref010","unstructured":"Guidance for industry, Bioanalytical method validation. 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