Physiologically Based Pharmacokinetic Modeling of Elexacaftor/Tezacaftor/Ivacaftor in Infants With Cystic Fibrosis
Year: 2026
Type: article
Abstract: 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.
DOI: 10.1002/psp4.70225
Authors: Ngoc Hoa Truong, Sihem Benaboud, Naïm Bouazza, Eric Deneuville, Anne Mornand, Philippe Reix, Mélanie Ribault, Pierre‐Régis Burgel, Léo Froelicher‐Bournaud, Steeve Rouillon, Mohammed Rohi Sanoufi, Gabrielle Lui, Saïk Urien, Jean‐Marc Tréluyer, Isabelle Sermet‐Gaudelus, Frantz Foissac, Modul‐CF study group
Institutions: Inserm, Université Paris Cité, Hôpital Cochin, Assistance Publique – Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Pharmacologie et évaluation thérapeutiques chez l'enfant et la femme enceinte, Centre d'Investigation Clinique Mère-Enfant Necker Cochin Paris Centre, Centre Hospitalier Universitaire de Rennes, University Hospital of Geneva, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Institut Cochin, Hôpital Necker-Enfants Malades, Institut Necker Enfants Malades
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,140
OpenAlex ID: W7162126257