{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T03:28:16Z","timestamp":1761017296170},"reference-count":25,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,3,19]],"date-time":"2020-03-19T00:00:00Z","timestamp":1584576000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100002491","name":"Bristol-Myers Squibb","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002491","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010877","name":"ViiV Healthcare","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010877","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004330","name":"GlaxoSmithKline","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004330","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2020,7]]},"abstract":"<jats:p>Fostemsavir, a prodrug of human immunodeficiency virus attachment inhibitor temsavir (TMR), is in phase III development in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type I (HIV\u20101) infection in heavily treatment\u2010experienced adults with multidrug\u2010resistant HIV\u20101 infection for whom it is otherwise not possible to construct a suppressive antiviral regimen due to resistance, intolerance, or safety considerations. The proarrhythmic potential of fostemsavir was studied in a thorough QT study and exposure\u2013response modeling was performed at therapeutic and supratherapeutic concentrations of TMR. Fostemsavir 1,200\u00a0mg b.i.d. did not result in a clinically meaningful change from placebo in baseline\u2010adjusted Fridericia\u2010corrected QTc (ddQTcF); however, at a supratherapeutic dose of 2,400\u00a0mg b.i.d., the upper bound of the two\u2010sided 90% confidence interval (CI) of ddQTcF was 13.2\u00a0msec, exceeding the clinically important 10\u00a0msec threshold. A linear model of ddQTcF as a function of TMR plasma concentrations described these observations. Based on simulations with this model, TMR concentrations up to 7,500\u00a0ng\/mL are expected to have an upper 90% CI bound for QTcF\u00a0\u2264\u00a010\u00a0msec. This concentration is 4.2\u2010fold higher than the geometric mean TMR peak plasma concentration (C<jats:sub>max<\/jats:sub>) of 1,770\u00a0ng\/mL in heavily treatment\u2010experienced HIV\u20101 infected patients administered fostemsavir 600\u00a0mg b.i.d. in the phase III BRIGHTE study (NCT02362503).<\/jats:p>","DOI":"10.1111\/cts.12763","type":"journal-article","created":{"date-parts":[[2020,2,6]],"date-time":"2020-02-06T14:31:02Z","timestamp":1580999462000},"page":"769-776","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Effects of Temsavir, Active Moiety of Antiretroviral Agent Fostemsavir, on QT Interval: Results From a Phase I Study and an Exposure\u2013Response Analysis"],"prefix":"10.1111","volume":"13","author":[{"given":"Chakradhar","family":"Lagishetty","sequence":"first","affiliation":[{"name":"GlaxoSmithKline Collegeville Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katy","family":"Moore","sequence":"additional","affiliation":[{"name":"ViiV Healthcare Research Triangle Park North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Ackerman","sequence":"additional","affiliation":[{"name":"ViiV Healthcare Branford Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cyril","family":"Llamoso","sequence":"additional","affiliation":[{"name":"ViiV Healthcare Branford Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mindy","family":"Magee","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline Collegeville Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,3,19]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.7b01337"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.24726"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.23476"},{"key":"e_1_2_10_4_1","unstructured":"Gorycki P.et al.Pharmacokinetics metabolism and excretion of radiolabelled fostemsavir administered with or without ritonavir in healthy male subjects. 19th International Workshop on Clinical Pharmacology of Antiviral Therapy; Baltimore MD USA; May 22\u201324 Abstract 42 (2018)."},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00426-12"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00513-13"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkt412"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3018(15)00177-0"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02503-15"},{"key":"e_1_2_10_10_1","unstructured":"Nettles R.et al.Single and multiple dose pharmacokinetics and safety in non\u2010HIV\u2010infected healthy subjects dosed with BMS\u2010663068 an oral HIV attachment inhibitor. 12th International Workshop on Clinical Pharmacology of HIV Therapy; Miami FL USA; April 13\u201315 Abstract O_04 (2011)."},{"key":"e_1_2_10_11_1","unstructured":"Janssen Pharmaceutical Companies.Edurant\u00ae; (rilpivirine) [package insert]. U.S. Food and Drug Administration (Drugs@FDA.com). U.S. Food and Drug Administration Website. <https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2011\/202022s000lbl.pdf>. Accessed August 28 2019."},{"key":"e_1_2_10_12_1","unstructured":"Abbvie Inc.KALETRA\u00ae (lopinavir and ritonavir) [package insert]. U.S. Food and Drug Administration (Drugs@FDA.com). U.S. Food and Drug Administration Website. <https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2019\/021251s057 021906s052lbl.pdf>. Accessed August 28 2019."},{"key":"e_1_2_10_13_1","unstructured":"International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline E14: The Clinical Evaluation of QT\/QTc Interval Prolongation and Proarrhythmic Potential for Non\u2010Antiarrhythmic Drugs.<https:\/\/www.ich.org\/fileadmin\/Public_Web_Site\/ICH_Products\/Guidelines\/Efficacy\/E14\/E14_Guideline.pdf> (May2005). Accessed March 11 2019."},{"key":"e_1_2_10_14_1","first-page":"149","article-title":"Experimental designs balanced for the estimation of residual effects of treatments","volume":"2","author":"Williams E.J.","year":"1949","journal-title":"Aus. J. Sci. Res."},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0954-6820.1920.tb18266.x"},{"key":"e_1_2_10_16_1","first-page":"353","article-title":"An analysis of the time\u2010relations of the electrocardiograms","volume":"7","author":"Bazett H.C.","year":"1920","journal-title":"Heart"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.2517-6161.1995.tb02031.x"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.04914-14"},{"key":"e_1_2_10_19_1","first-page":"447","article-title":"A simulation study of power in thorough QT\/QTc studies and a normal approximation for planning purposes","volume":"39","author":"Hosmane B.","year":"2005","journal-title":"Ther. Innov. Regul. Sci."},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270010376962"},{"key":"e_1_2_10_21_1","unstructured":"Vakkalagadda B.et al.HIV\u20101 attachment inhibitor prodrug BMS\u2010663068: interactions with cobicistat and darunavir+cobicistat. ICAAC\/ICC 2015; San Diego CA USA; September 17\u201321 Abstract 1676 (2015)."},{"key":"e_1_2_10_22_1","doi-asserted-by":"crossref","unstructured":"Moore K.et al.Fostemsavir drug\u2010drug interaction profile an attachment inhibitor and oral prodrug of temsavir for heavily treatment\u2010experienced HIV\u20101 infected patients. ID Week 2019; Washington DC USA; October 2\u20136 Abstract 2500.","DOI":"10.1093\/ofid\/ofz360.2178"},{"key":"e_1_2_10_23_1","unstructured":"Lataillade M.et al.Week 96 safety and efficacy of the novel HIV\u20101 attachment inhibitor prodrug fostemsavir in heavily treatment\u2010experienced participants infected with multi\u2010drug resistant HIV\u20101 (BRIGHTE Study). International AIDS Conference on HIV Science (IAS) 2019; Mexico City Mexico; July 21\u201324."},{"key":"e_1_2_10_24_1","unstructured":"Moore K.et al.Impact of mild moderate and severe renal impairment and hemodialysis on temsavir pharmacokinetics following oral administration of fostemsavir an attachment inhibitor for heavily treatment experienced HIV\u20101 infected patients. HIV Drug Therapy 2018; Glasgow UK; October 28\u201331. Poster 261."},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofx163.1086"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcts.12763","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.12763","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cts.12763","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.12763","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,5]],"date-time":"2023-09-05T08:36:41Z","timestamp":1693903001000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.12763"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,19]]},"references-count":25,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2020,7]]}},"alternative-id":["10.1111\/cts.12763"],"URL":"https:\/\/doi.org\/10.1111\/cts.12763","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,19]]},"assertion":[{"value":"2019-11-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-01-01","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-03-19","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}