{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T05:08:08Z","timestamp":1768280888367,"version":"3.49.0"},"reference-count":23,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T00:00:00Z","timestamp":1714521600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>It is critical to understand the impact of significant physiological changes during pregnancy on the extent of maternal and fetal drug exposure. Fostemsavir (FTR) is a prodrug of temsavir (TMR) and is approved in combination with other antiretrovirals for multi\u2010drug\u2010resistant human immunodeficiency virus (HIV) infections. This physiologically based pharmacokinetic model (PBPK) study was used to estimate TMR PK in pregnant populations during each trimester of pregnancy to inform FTR dosing. A PBPK model was developed and validated for TMR using PK data collected following intravenous TMR and oral FTR dosing (immediate\u2010release and extended\u2010release tablets) in healthy volunteers. Predicted TMR concentration\u2013time profiles accurately predicted the reported clinical data and variability in healthy (dense data) and pregnant (sparse data) populations. Predicted versus observed TMR geometric mean (CV%) clearance following intravenous administration was 18.01 (29) versus 17 (21) (L\/h). Predicted versus observed TMR AUC<jats:sub>0\u2013inf<\/jats:sub> (ng.h\/mL) in healthy volunteers following FTR administration of the extended\u2010release tablet were 9542 (66) versus 7339 (33). The validated TMR PBPK model was then applied to predict TMR PK in a population of pregnant individuals during each trimester. Simulations showed TMR AUC in pregnant individuals receiving FTR 600\u2009mg twice daily was decreased by 25% and 38% in the second and third trimesters, respectively. However, TMR exposure remained within the range observed in nonpregnant adults with no need for dose adjustment. The current PBPK model can also be applied for the prediction of local tissue concentrations and drug\u2013drug interactions in pregnancy.<\/jats:p>","DOI":"10.1002\/psp4.13156","type":"journal-article","created":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T11:04:40Z","timestamp":1714561480000},"page":"1881-1892","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Development of a physiologically based pharmacokinetic model of fostemsavir and its pivotal application to support dosing in pregnancy"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1791-9390","authenticated-orcid":false,"given":"Farzaneh","family":"Salem","sequence":"first","affiliation":[{"name":"Drug Metabolism and Pharmacokinetics GlaxoSmithKline, R&amp;D  Stevenage UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dung","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Drug Metabolism and Pharmacokinetics GlaxoSmithKline R&amp;D  Collegeville Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Bush","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology ViiV Research &amp; Development  Triangle Park North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katy P.","family":"Moore","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Modeling and Simulation Allucent  Cary North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3132-7348","authenticated-orcid":false,"given":"Jennypher","family":"Mudunuru","sequence":"additional","affiliation":[{"name":"Drug Metabolism and Pharmacokinetics GlaxoSmithKline, R&amp;D  Stevenage UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7524-2800","authenticated-orcid":false,"given":"Konstantinos","family":"Stamatopoulos","sequence":"additional","affiliation":[{"name":"Biopharmaceutics, DPD, MDS GlaxoSmithKline, David Jack Centre, Park Road  Ware UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2846-5796","authenticated-orcid":false,"given":"Nilay","family":"Thakkar","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Modeling and Simulation GlaxoSmithKline R&amp;D  Collegeville Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9979-8267","authenticated-orcid":false,"given":"Kunal S.","family":"Taskar","sequence":"additional","affiliation":[{"name":"Drug Metabolism and Pharmacokinetics GlaxoSmithKline, R&amp;D  Stevenage UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,5]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"BMS.A Multi\u2010arm Phase 3 Randomized Placebo Controlled Double Blind Clinical Trial to Investigate the Efficacy and Safety of BMS\u2010663068\/GSK3684934 in Heavily Treatment Experienced Subjects Infected with Multi\u2010drug Resistant HIV\u20101.2022."},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.23476"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.7b01337"},{"key":"e_1_2_10_5_1","unstructured":"FDA & C.F.D.E.A. Research.Biotransformation of [14C]BMS\u2010663068 after Oral administration to mice rats dogs and humans 178.2019."},{"key":"e_1_2_10_6_1","unstructured":"930105929\u2010AI438075 B.Study of the Absolute Bioavailability of BMS\u2010626529 in Healthy Subjects Followinjg Oral Dosing of BMS\u2010663068 and Intravenous Dosing of BMS\u2010626529. (Report no. 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