Academic Journal
Physiologically Based Pharmacokinetic Modeling of Elexacaftor/Tezacaftor/Ivacaftor in Infants With Cystic Fibrosis.
| Τίτλος: | Physiologically Based Pharmacokinetic Modeling of Elexacaftor/Tezacaftor/Ivacaftor in Infants With Cystic Fibrosis. |
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| Συγγραφείς: | Truong NH; Inserm, Pharmacologie et évaluations Des thérapeutiques Chez L'enfant et la Femme Enceinte, Université Paris Cité, Paris, France.; Service De Pharmacologie Périnatale, Pédiatrique et Adulte, Hôpital Cochin, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux De Paris, Paris, France., Benaboud S; Inserm, Pharmacologie et évaluations Des thérapeutiques Chez L'enfant et la Femme Enceinte, Université Paris Cité, Paris, France.; Service De Pharmacologie Périnatale, Pédiatrique et Adulte, Hôpital Cochin, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux De Paris, Paris, France., Bouazza N; Inserm, Pharmacologie et évaluations Des thérapeutiques Chez L'enfant et la Femme Enceinte, Université Paris Cité, Paris, France.; Unité de Recherche Clinique Necker Cochin, Paris, France.; CIC-1419 Inserm, Cochin-Necker, Paris, France., Deneuville E; Centre de Ressources et de Compétences de la Mucoviscidose, Hôpitaux Universitaires de Rennes, Rennes, France., Mornand A; Department of Women, Child and Adolescent, Pediatric Pulmonology, University Geneva Hospitals, Geneva, Switzerland., Reix P; Centre de Ressources et de Compétences Pour la Mucoviscidose, Site Pédiatrique, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Lyon, France., Ribault M; Centre de Ressources et de Compétences de la Mucoviscidose, Hôpitaux Universitaires de Rennes, Rennes, France., Burgel PR; Institut Cochin, Inserm U1016, Université Paris Cité, Paris, France.; Department of Respiratory Medicine and French National Cystic Fibrosis Reference Center, Hôpital Cochin, AP-HP, Paris, France., Froelicher-Bournaud L; Inserm, Pharmacologie et évaluations Des thérapeutiques Chez L'enfant et la Femme Enceinte, Université Paris Cité, Paris, France.; Service De Pharmacologie Périnatale, Pédiatrique et Adulte, Hôpital Cochin, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux De Paris, Paris, France., Rouillon S; Inserm, Pharmacologie et évaluations Des thérapeutiques Chez L'enfant et la Femme Enceinte, Université Paris Cité, Paris, France., Sanoufi MR; Inserm, Pharmacologie et évaluations Des thérapeutiques Chez L'enfant et la Femme Enceinte, Université Paris Cité, Paris, France.; Service De Pharmacologie Périnatale, Pédiatrique et Adulte, Hôpital Cochin, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux De Paris, Paris, France., Lui G; Inserm, Pharmacologie et évaluations Des thérapeutiques Chez L'enfant et la Femme Enceinte, Université Paris Cité, Paris, France., Urien S; Inserm, Pharmacologie et évaluations Des thérapeutiques Chez L'enfant et la Femme Enceinte, Université Paris Cité, Paris, France.; Unité de Recherche Clinique Necker Cochin, Paris, France.; CIC-1419 Inserm, Cochin-Necker, Paris, France., Tréluyer JM; Inserm, Pharmacologie et évaluations Des thérapeutiques Chez L'enfant et la Femme Enceinte, Université Paris Cité, Paris, France.; Service De Pharmacologie Périnatale, Pédiatrique et Adulte, Hôpital Cochin, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux De Paris, Paris, France.; Unité de Recherche Clinique Necker Cochin, Paris, France.; CIC-1419 Inserm, Cochin-Necker, Paris, France., Sermet-Gaudelus I; Hôpital Necker Enfants Malades, Centre De Référence Maladies Rares Mucoviscidose et Maladies Apparentées, Paris, France.; Université de Paris Cité, Paris, France.; Institut Necker Enfants Malades, INSERM U1151, Paris, France., Foissac F; Inserm, Pharmacologie et évaluations Des thérapeutiques Chez L'enfant et la Femme Enceinte, Université Paris Cité, Paris, France.; Unité de Recherche Clinique Necker Cochin, Paris, France.; CIC-1419 Inserm, Cochin-Necker, Paris, France. |
| Συλλογικό Έργο: | Modul‐CF study group |
| Πηγή: | CPT: pharmacometrics & systems pharmacology [CPT Pharmacometrics Syst Pharmacol] 2026 Jun; Vol. 15 (6), pp. e70225. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Wiley Country of Publication: United States NLM ID: 101580011 Publication Model: Print Cited Medium: Internet ISSN: 2163-8306 (Electronic) Linking ISSN: 21638306 NLM ISO Abbreviation: CPT Pharmacometrics Syst Pharmacol Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2015- : Hoboken, NJ : Wiley Original Publication: New York, NY : Nature Pub. Group |
| Ιατρικοί όροι (MeSH): | Cystic Fibrosis*/drug therapy , Cystic Fibrosis*/metabolism , Quinolones*/pharmacokinetics , Quinolones*/administration & dosage , Aminophenols*/pharmacokinetics , Aminophenols*/administration & dosage , Indoles*/pharmacokinetics , Indoles*/administration & dosage , Pyrazoles*/pharmacokinetics , Pyrazoles*/administration & dosage , Pyridines*/pharmacokinetics , Pyridines*/administration & dosage , Benzodioxoles*/pharmacokinetics , Benzodioxoles*/administration & dosage , Chloride Channel Agonists*/pharmacokinetics , Chloride Channel Agonists*/administration & dosage , Models, Biological*, Humans ; Infant ; Drug Combinations ; Male ; Female ; Quinolines |
| Περίληψη: | Ivacaftor is the only cystic fibrosis transmembrane conductance regulator modulator approved for infants ≥ 1 month. The elexacaftor/tezacaftor/ivacaftor combination, approved for children aged ≥ 2 years, 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 month to < 2 years using physiologically based pharmacokinetic modeling (PBPK) and to determine whether age- 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 2-18 years via the Simcyp Pediatric Simulator and the Uprety-Wahlström cytochrome-P450 3A4 ontogeny method to simulate the current elexacaftor/tezacaftor/ivacaftor dosing regimen. FDA-approved ivacaftor monotherapy dosing was evaluated in children 1 month to < 2 years and subsequently used to guide the extrapolation of elexacaftor/tezacaftor/ivacaftor combination dosing regimens. The overall workflow was validated using in vivo pharmacokinetic data or literature-based sources. Elexacaftor/tezacaftor/ivacaftor PBPK models for adults and children ≥ 2 years were validated against observed clinical pharmacokinetic data. Simulations of elexacaftor/tezacaftor/ivacaftor doses based on ivacaftor monotherapy in infants < 2 years matched adult-reported levels, except in infants 1-2 months, who showed lower exposures, and in those weighing ≥ 14 kg, who may experience higher exposures. Using PBPK modeling, supported by clinical pharmacokinetic data, this study explores elexacaftor/tezacaftor/ivacaftor dosing in children under 2 years. The findings offer preliminary dosing guidance, pending confirmation in larger clinical studies, with therapeutic drug monitoring recommended to guide treatment. (© 2026 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.) |
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| Contributed Indexing: | Investigator: M Baravalle; M Barboura; L Benhalla; K Bennour; K Bessaci; A Bessou; T Bihouée; AS Bonnel; N Bouleghem; S Bui; F Chedevergne; H Corvol; L Cosson; L Couderc; ML Dalphin; P De Carli; E Deneuville; P Foucaud; A Gabsi; E Gachelin; F Hassani; V Houdouin; F Huet; M Jamin; K Kaba; G Labbé; J Languepin; M Laurans; C Léréna; A Letierce; C Livrozet; C Marguet; L Mély; R Messaoudi; M Mittaine; C Ohlmann; C Périsson; T Perrin; C Piccini-Bailly; C Rames; P Reix; N Rémus; A Ronayette; D Sahki; M Scalbert; I Sermet; F Socchi; N Stremler; A Tatopoulos; G Thouvenin; T Toin; F Troussier; L Weiss; MC Werck-Galois; N Wizla Keywords: CFTR modulators; PBPK; cystic fibrosis; infants; therapeutic drug monitoring |
| Substance Nomenclature: | 0 (Quinolones) 0 (Aminophenols) 0 (Indoles) 0 (Drug Combinations) 0 (elexacaftor, ivacaftor, tezacaftor drug combination) 0 (Pyrazoles) 0 (Pyridines) 0 (Benzodioxoles) 0 (Chloride Channel Agonists) 0 (Quinolines) |
| Entry Date(s): | Date Created: 20260522 Date Completed: 20260717 Latest Revision: 20260726 |
| Update Code: | 20260726 |
| PubMed Central ID: | PMC13239390 |
| DOI: | 10.1002/psp4.70225 |
| PMID: | 42170795 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 2163-8306 |
|---|---|
| DOI: | 10.1002/psp4.70225 |