{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T03:23:36Z","timestamp":1781839416132,"version":"3.54.5"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH\/NIDCD"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Congenital cytomegalovirus (cCMV) infection is the most common cause of nonhereditary pediatric sensorineural hearing loss (SNHL). Importantly, cCMV is treatable, with the primary option being ganciclovir (GCV) or its orally bioavailable pro-drug valganciclovir (VGCV). A challenge for treating cCMV is the elevated risk for neutropenia associated with standard dosing. Optimizing and individualizing (V)GCV dosing could ameliorate the risk of neutropenia and improve efficacy but requires an understanding of the complex intracellular phosphorylation processes that govern the formation of the active GCV-triphosphate (GCV-TP) moiety. This study utilizes dried blood spot (DBS) samples from infants with cCMV to quantify GCV-TP and explore the kinetics of GCV-TP in this matrix.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>DBS samples were collected from infants with cCMV infection receiving 16\u2005mg\/kg VGCV twice daily as part of either a randomized, placebo-controlled clinical trial (ValEAR) or an open-label PK study. GCV-TP concentrations in DBS were determined using LC-MS\/MS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Data indicate that GCV-TP is long-lived in DBS, with a half-life approximating 21\u2005days. This leads to extensive GCV-TP accumulation in this matrix (primarily consisting of erythrocytes), with an expected approximately 62-fold difference in first-dose and steady-state concentrations. Simulated data highlight the potential for DBS GCV-TP to be used as an objective adherence marker.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings underscore the need to define the kinetics of GCV-TP in cell matrices relevant to its activity to determine appropriate VGCV dosing strategies in this population and establish safe and define effective therapeutic concentration targets.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/infdis\/jiaf633","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T13:16:47Z","timestamp":1765372607000},"page":"e1040-e1045","source":"Crossref","is-referenced-by-count":4,"title":["Intracellular Ganciclovir Triphosphate Concentrations in Children With Congenital Cytomegalovirus Infection"],"prefix":"10.1093","volume":"233","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6546-918X","authenticated-orcid":false,"given":"Brent","family":"Lindquist-Kleissler","sequence":"first","affiliation":[{"name":"Center for Human Toxicology, Department of Pharmacology and Toxicology, University of Utah , Salt Lake City, Utah ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2885-7108","authenticated-orcid":false,"given":"Peter","family":"Kfoury","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, University of Utah , Salt Lake City, Utah ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3155-1695","authenticated-orcid":false,"given":"Keith T","family":"Kuo","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, University of Utah , Salt Lake City, Utah ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron","family":"Elwood","sequence":"additional","affiliation":[{"name":"Center for Human Toxicology, Department of Pharmacology and Toxicology, University of Utah , Salt Lake City, Utah ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashlea","family":"Wilkes","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, University of Utah , Salt Lake City, Utah ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9089-3014","authenticated-orcid":false,"given":"Albert H","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, University of Utah , Salt Lake City, Utah ,","place":["USA"]},{"name":"Department of Pediatrics, University of Utah , Salt Lake City, Utah ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3629-7902","authenticated-orcid":false,"given":"Joseph E","family":"Rower","sequence":"additional","affiliation":[{"name":"Center for Human Toxicology, Department of Pharmacology and Toxicology, University of Utah , Salt Lake City, Utah ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,12,11]]},"reference":[{"key":"2026042913523396000_jiaf633-B1","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1080\/00365540802308431","article-title":"Congenital CMV infection: prevalence in newborns and the impact on hearing deficit","volume":"40","author":"Engman","year":"2008","journal-title":"Scand J Infect Dis"},{"key":"2026042913523396000_jiaf633-B2","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/rmv.535","article-title":"Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection","volume":"17","author":"Kenneson","year":"2007","journal-title":"Rev Med Virol"},{"key":"2026042913523396000_jiaf633-B3","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1542\/peds.2006-3441","article-title":"Newborn hearing screening and detection of congenital cytomegalovirus infection","volume":"121","author":"Stehel","year":"2008","journal-title":"Pediatrics"},{"key":"2026042913523396000_jiaf633-B4","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.jcv.2005.09.016","article-title":"Congenital cytomegalovirus (CMV) infection and hearing deficit","volume":"35","author":"Fowler","year":"2006","journal-title":"J Clin Virol"},{"key":"2026042913523396000_jiaf633-B5","volume-title":"Red book: 2024\u20132027 report of the committee on infectious diseases","author":"American Academy of Pediatrics Committee on Infectious Diseases","year":"2024"},{"key":"2026042913523396000_jiaf633-B6","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1086\/528376","article-title":"Pharmacokinetic and pharmacodynamic assessment of oral valganciclovir in the treatment of symptomatic congenital cytomegalovirus disease","volume":"197","author":"Kimberlin","year":"2008","journal-title":"J Infect Dis"},{"key":"2026042913523396000_jiaf633-B7","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/S0022-3476(03)00192-6","article-title":"Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial","volume":"143","author":"Kimberlin","year":"2003","journal-title":"J Pediatr"},{"key":"2026042913523396000_jiaf633-B8","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1056\/NEJMoa1404599","article-title":"Valganciclovir for symptomatic congenital cytomegalovirus disease","volume":"372","author":"Kimberlin","year":"2015","journal-title":"N Engl J Med"},{"key":"2026042913523396000_jiaf633-B9","doi-asserted-by":"crossref","first-page":"S22","DOI":"10.1016\/j.jcv.2009.08.012","article-title":"Neurodevelopmental outcomes following ganciclovir therapy in symptomatic congenital cytomegalovirus infections involving the central nervous system","volume":"46","author":"Oliver","year":"2009","journal-title":"J Clin Virol"},{"key":"2026042913523396000_jiaf633-B10","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1128\/AAC.31.3.452","article-title":"Toxicity of 3'-azido-3\u2032-deoxythymidine and 9-(1, 3-dihydroxy-2-propoxymethyl) guanine for normal human hematopoietic progenitor cells in vitro","volume":"31","author":"Sommadossi","year":"1987","journal-title":"Antimicrob Agents Chemother"},{"key":"2026042913523396000_jiaf633-B11","first-page":"72","article-title":"Safety of alternative antiviral agents for neonatal herpes simplex virus encephalitis and disseminated infection","volume":"19","author":"Wang","year":"2014","journal-title":"J Pediatr Pharmacol Ther"},{"key":"2026042913523396000_jiaf633-B12","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1097\/INF.0000000000002079","article-title":"Hematologic adverse events associated with prolonged valganciclovir treatment in congenital cytomegalovirus infection","volume":"38","author":"Ziv","year":"2019","journal-title":"Pediatr Infect Dis J"},{"key":"2026042913523396000_jiaf633-B13","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1093\/icvts\/ivx226","article-title":"Cytomegalovirus infection in living-donor and cadaveric lung transplantations","volume":"25","author":"Ohata","year":"2017","journal-title":"Interact CardioVasc Thorac Surg"},{"key":"2026042913523396000_jiaf633-B14","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1001\/jama.2023.9106","article-title":"Letermovir vs valganciclovir for prophylaxis of cytomegalovirus in high-risk kidney transplant recipients: a randomized clinical trial","volume":"330","author":"Limaye","year":"2023","journal-title":"JAMA"},{"key":"2026042913523396000_jiaf633-B15","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1002\/ohn.670","article-title":"Congenital cytomegalovirus testing outcomes from the ValEAR trial","volume":"170","author":"Orb","year":"2024","journal-title":"Otolaryngol Head Neck Surg"},{"key":"2026042913523396000_jiaf633-B16","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.jpba.2016.01.038","article-title":"Application of an intracellular assay for determination of tenofovir-diphosphate and emtricitabine-triphosphate from erythrocytes using dried blood spots","volume":"122","author":"Zheng","year":"2016","journal-title":"J Pharmaceut Biomed Anal"},{"key":"2026042913523396000_jiaf633-B17","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.jpba.2011.05.039","article-title":"Determination of nucleoside analog mono-, di-, and tri-phosphates in cellular matrix by solid phase extraction and ultra-sensitive LC\u2013MS\/MS detection","volume":"56","author":"Bushman","year":"2011","journal-title":"J Pharmaceut Biomed Anal"},{"key":"2026042913523396000_jiaf633-B18","doi-asserted-by":"crossref","first-page":"113181","DOI":"10.1016\/j.jpba.2020.113181","article-title":"Validation of an assay for quantifying ganciclovir in dried blood spots","volume":"184","author":"Rower","year":"2020","journal-title":"J Pharm Biomed Anal"},{"key":"2026042913523396000_jiaf633-B19","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1093\/jac\/dkv342","article-title":"Plasma and intracellular exposure to ganciclovir in adult renal transplant recipients: is there an association with haematological toxicity?","volume":"71","author":"Billat","year":"2016","journal-title":"J Antimicrob Chemother"},{"key":"2026042913523396000_jiaf633-B20","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1097\/TP.0b013e3182000042","article-title":"Ganciclovir pharmacokinetic parameters do not change when extending valganciclovir cytomegalovirus prophylaxis from 100 to 200 days","volume":"90","author":"Welker","year":"2010","journal-title":"Transplantation"},{"key":"2026042913523396000_jiaf633-B21","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1128\/AAC.02311-13","article-title":"Metabolism of cyclopropavir and ganciclovir in human cytomegalovirus-infected cells","volume":"58","author":"Gentry","year":"2014","journal-title":"Antimicrob Agents Chemother"},{"key":"2026042913523396000_jiaf633-B22","doi-asserted-by":"crossref","first-page":"2473","DOI":"10.1073\/pnas.82.8.2473","article-title":"Metabolic activation of the nucleoside analog 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy]methyl)guanine in human diploid fibroblasts infected with human cytomegalovirus","volume":"82","author":"Biron","year":"1985","journal-title":"Proc Natl Acad Sci"},{"key":"2026042913523396000_jiaf633-B23","doi-asserted-by":"crossref","first-page":"S490","DOI":"10.1093\/clinids\/10.Supplement_3.S490","article-title":"Antiviral activity and mechanism of action of ganciclovir","volume":"10","author":"Matthews","year":"1988","journal-title":"Rev Infect Dis"},{"key":"2026042913523396000_jiaf633-B24","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1093\/jac\/dkq447","article-title":"Pharmacological considerations for tenofovir and emtricitabine to prevent HIV infection","volume":"66","author":"Anderson","year":"2011","journal-title":"J Antimicrob Chemother"},{"key":"2026042913523396000_jiaf633-B25","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1038\/sj.clpt.6100150","article-title":"Ganciclovir population pharmacokinetics in neonates following intravenous administration of ganciclovir and oral administration of a liquid valganciclovir formulation","volume":"81","author":"Acosta","year":"2007","journal-title":"Clin Pharmacol Therapeut"},{"key":"2026042913523396000_jiaf633-B26","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1093\/jpids\/piw008","article-title":"Therapeutic drug monitoring of ganciclovir treatment for cytomegalovirus infections among immunocompromised children","volume":"5","author":"Stockmann","year":"2016","journal-title":"J Pediatr Infect Dis Soc"},{"key":"2026042913523396000_jiaf633-B27","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1097\/01.TP.0000164512.99703.AD","article-title":"Pharmacodynamics of oral ganciclovir and valganciclovir in solid organ transplant recipients","volume":"79","author":"Wiltshire","year":"2005","journal-title":"Transplantation"},{"key":"2026042913523396000_jiaf633-B28","doi-asserted-by":"crossref","first-page":"100892","DOI":"10.1016\/j.lanepe.2024.100892","article-title":"Consensus recommendation for prenatal, neonatal and postnatal management of congenital cytomegalovirus infection from the European congenital infection initiative (ECCI)","volume":"40","author":"Leruez-Ville","year":"2024","journal-title":"Lancet Reg Health\u2013Europe"},{"key":"2026042913523396000_jiaf633-B29","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1097\/TP.0000000000005374","article-title":"The Fourth International Consensus Guidelines on the management of cytomegalovirus in solid organ transplantation","volume":"109","author":"Kotton","year":"2025","journal-title":"Transplantation"},{"key":"2026042913523396000_jiaf633-B30","doi-asserted-by":"crossref","first-page":"107537","DOI":"10.1016\/j.ijantimicag.2025.107537","article-title":"The importance of drug exposure in the development of cytomegalovirus resistance","volume":"66","author":"Lynch","year":"2025","journal-title":"Int J Antimicrob Agents"},{"key":"2026042913523396000_jiaf633-B31","doi-asserted-by":"crossref","first-page":"8039","DOI":"10.1073\/pnas.140123497","article-title":"Prediction of cytomegalovirus load and resistance patterns after antiviral chemotherapy","volume":"97","author":"Emery","year":"2000","journal-title":"Proc Natl Acad Sci"},{"key":"2026042913523396000_jiaf633-B32","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.jchromb.2014.11.032","article-title":"Measurement of intracellular ribavirin mono-, di-and triphosphate using solid phase extraction and LC\u2013MS\/MS quantification","volume":"978-979","author":"Jimmerson","year":"2015","journal-title":"J Chromatogr B"},{"key":"2026042913523396000_jiaf633-B33","doi-asserted-by":"crossref","first-page":"7671","DOI":"10.1128\/AAC.01693-15","article-title":"Validation and application of a liquid chromatography-tandem mass spectrometry method to determine the concentrations of sofosbuvir anabolites in cells","volume":"59","author":"Rower","year":"2015","journal-title":"Antimicrob Agents Chemother"},{"key":"2026042913523396000_jiaf633-B34","doi-asserted-by":"crossref","first-page":"3449","DOI":"10.1007\/s00216-015-8554-0","article-title":"Liquid chromatography tandem mass spectrometry quantitation of intracellular concentrations of ganciclovir and its phosphorylated forms","volume":"407","author":"Billat","year":"2015","journal-title":"Anal Bioanal Chem"},{"key":"2026042913523396000_jiaf633-B35","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1089\/aid.2016.0008","article-title":"Intracellular tenofovir and emtricitabine anabolites in genital, rectal, and blood compartments from first dose to steady state","volume":"32","author":"Seifert","year":"2016","journal-title":"AIDS Res Hum Retrovir"}],"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\/jiaf633\/65848152\/jiaf633.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/article-pdf\/233\/4\/e1040\/65848152\/jiaf633.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/article-pdf\/233\/4\/e1040\/65848152\/jiaf633.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T17:52:43Z","timestamp":1777485163000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jid\/article\/233\/4\/e1040\/8377515"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,11]]},"references-count":35,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,12,11]]},"published-print":{"date-parts":[[2026,4,29]]}},"URL":"https:\/\/doi.org\/10.1093\/infdis\/jiaf633","relation":{},"ISSN":["0022-1899","1537-6613"],"issn-type":[{"value":"0022-1899","type":"print"},{"value":"1537-6613","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,4,15]]},"published":{"date-parts":[[2025,12,11]]}}}