{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T10:11:27Z","timestamp":1792145487278,"version":"4.4.0"},"reference-count":39,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Ivacaftor is the only cystic fibrosis transmembrane conductance regulator modulator approved for infants \u2265\u20091\u2009month. The elexacaftor\/tezacaftor\/ivacaftor combination, approved for children aged \u2265\u20092\u2009years, has been shown to significantly slow CF progression. Expanding elexacaftor\/tezacaftor\/ivacaftor use to infants may offer additional therapeutic benefits. This study aims to predict elexacaftor\/tezacaftor\/ivacaftor pharmacokinetics in infants aged 1\u2009month to &lt;\u20092\u2009years using physiologically based pharmacokinetic modeling (PBPK) and to determine whether age\u2010 and weight elexacaftor\/tezacaftor\/ivacaftor doses, extrapolated from ivacaftor monotherapy, produce drug exposures comparable to adult levels. Adult elexacaftor\/tezacaftor\/ivacaftor PBPK published models were first reproduced using Simcyp. These models were scaled to children aged 2\u201318\u2009years via the Simcyp Pediatric Simulator and the Uprety\u2013Wahlstr\u00f6m cytochrome\u2010P450 3A4 ontogeny method to simulate the current elexacaftor\/tezacaftor\/ivacaftor dosing regimen. FDA\u2010approved ivacaftor monotherapy dosing was evaluated in children 1\u2009month to &lt;\u20092\u2009years and subsequently used to guide the extrapolation of elexacaftor\/tezacaftor\/ivacaftor combination dosing regimens. The overall workflow was validated using in\u00a0vivo pharmacokinetic data or literature\u2010based sources. Elexacaftor\/tezacaftor\/ivacaftor PBPK models for adults and children \u2265\u20092\u2009years were validated against observed clinical pharmacokinetic data. Simulations of elexacaftor\/tezacaftor\/ivacaftor doses based on ivacaftor monotherapy in infants &lt;\u20092\u2009years matched adult\u2010reported levels, except in infants 1\u20132\u2009months, who showed lower exposures, and in those weighing \u2265\u200914\u2009kg, who may experience higher exposures. Using PBPK modeling, supported by clinical pharmacokinetic data, this study explores elexacaftor\/tezacaftor\/ivacaftor dosing in children under 2\u2009years. The findings offer preliminary dosing guidance, pending confirmation in larger clinical studies, with therapeutic drug monitoring recommended to guide treatment.<\/jats:p>","DOI":"10.1002\/psp4.70225","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T09:45:18Z","timestamp":1779443118000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Physiologically Based Pharmacokinetic Modeling of Elexacaftor\/Tezacaftor\/Ivacaftor in Infants With Cystic Fibrosis"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6818-221X","authenticated-orcid":false,"given":"Ngoc Hoa","family":"Truong","sequence":"first","affiliation":[{"name":"Inserm, Pharmacologie et \u00e9valuations Des th\u00e9rapeutiques Chez L'enfant et la Femme Enceinte Universit\u00e9 Paris Cit\u00e9  Paris France"},{"name":"Service De Pharmacologie P\u00e9rinatale, P\u00e9diatrique et Adulte, H\u00f4pital Cochin, H\u00f4pital Europ\u00e9en Georges Pompidou, Assistance Publique H\u00f4pitaux De Paris  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sihem","family":"Benaboud","sequence":"additional","affiliation":[{"name":"Inserm, Pharmacologie et \u00e9valuations Des th\u00e9rapeutiques Chez L'enfant et la Femme Enceinte Universit\u00e9 Paris Cit\u00e9  Paris France"},{"name":"Service De Pharmacologie P\u00e9rinatale, P\u00e9diatrique et Adulte, H\u00f4pital Cochin, H\u00f4pital Europ\u00e9en Georges Pompidou, Assistance Publique H\u00f4pitaux De Paris  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na\u00efm","family":"Bouazza","sequence":"additional","affiliation":[{"name":"Inserm, Pharmacologie et \u00e9valuations Des th\u00e9rapeutiques Chez L'enfant et la Femme Enceinte Universit\u00e9 Paris Cit\u00e9  Paris France"},{"name":"Unit\u00e9 de Recherche Clinique Necker Cochin  Paris France"},{"name":"CIC\u20101419 Inserm, Cochin\u2010Necker  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Deneuville","sequence":"additional","affiliation":[{"name":"Centre de Ressources et de Comp\u00e9tences de la Mucoviscidose H\u00f4pitaux Universitaires de Rennes  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Mornand","sequence":"additional","affiliation":[{"name":"Department of Women, Child and Adolescent, Pediatric Pulmonology University Geneva Hospitals  Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Reix","sequence":"additional","affiliation":[{"name":"Centre de Ressources et de Comp\u00e9tences Pour la Mucoviscidose, Site P\u00e9diatrique, H\u00f4pital Femme M\u00e8re Enfant, Hospices Civils de Lyon  Lyon 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