Paulette Magnas 1, Naim Bouazza 1,2, Frantz Foissac 1,2, Saïk Urien 2, Léo Froelicher-Bournaud 1,3, Gabrielle Lui 1,4, Amit Ahire 1, Victoria Guillemart 4, Nicolas Carlier 5, Jennifer Da Silva 5, Johanna Fesenbeckh 5, Reem Kanaan 5, Isabelle Honoré 5, Clémence Martin 5,6, Jean-Marc Treluyer 1,2,3,4, Vassilis Tsatsaris 7, Pierre-Régis Burgel 5,6, Sihem Benaboud 1,3
1 U1343, Pharmacologie et évaluations thérapeutiques chez l'enfant et la femme enceinte, Inserm, Université Paris Cité (Paris, France), 2 Unité de Recherche Clinique, Université Paris Cité Necker/Cochin, Hôpital Tarnier (Paris, France), 3 Service de Pharmacologie Clinique, Hôpital Cochin, AP-HP, Groupe Hospitalier Paris Centre (Paris, France), 4 CIC-1419 Inserm, Hôpitaux Cochin-Necker (Paris, France), 5 Service de Pneumologie, Centre National de Référence de la Mucoviscidose, Hôpital Cochin, AP-HP (Paris, France), 6 Université Paris Cité, Institut Cochin, Inserm U1016 (Paris, France), 7 Université Paris Cité, Maternité Port Royal, AP-HP (Paris, France)
Objectives: Pregnancies among women with cystic fibrosis (CF) have increased markedly in the era of highly effective CFTR modulators, particularly with elexacaftor–tezacaftor–ivacaftor (ETI) [1, 2]. However, pregnancy introduces complex physiological and anatomical changes, including modifications in hepatic enzyme activity, plasma volume, protein binding, and organ blood flow, which can alter drug pharmacokinetics [3]. In parallel, increasing reports of placental transfer of ETI compounds raise important clinical questions regarding fetal exposure [4]. Despite the growing use of ETI in pregnancy, evidence-based guidance for dose management remains limited. Optimal dosing strategies are further complicated by the need to balance maternal therapeutic goals with potential fetal exposure. This raises critical questions regarding the intended therapeutic objective–whether the primary aim is to sustain maternal health, to provide in utero treatment; notably for in-utero management of meconium ileus in a fetus diagnosed with CF, or to address both concurrently. This represents an urgent unmet clinical need, as both maternal underexposure and excessive fetal exposure carry potential risks, including disease destabilization in the mother and developmental safety concerns for the fetus [5–7]. Gestational pharmacokinetic data remain limited, and no sponsor-led studies have yet defined optimal ETI dosing, assessed foetal exposure or maternal-foetal safety. These knowledge gaps warrant mechanistically informed investigation to support evidence-based treatment decisions and ensure safe and effective care. The aim of this study was to develop and validate an integrated maternal-fetal physiologically based pharmacokinetic (PBPK) model for ETI during pregnancy, incorporating ex vivo human placental transfer data and real-world clinical pharmacokientics.
Methods: Transplacental transfer parameters were derived from ex vivo term human placenta perfusion experiments and were estimated using mixed effects modeling in Monolix®. These empirically derived parameters were integrated in the pregnancy-specific ETI PBPK models in the Simcyp® simulator, accounting for gestation-dependent dynamic physiological changes. Model predictions were evaluated against observed maternal ETI concentrations (n=46) across trimesters (T1 = 9, T2 = 18, T3 = 19), obtained from 15 pregnancies enrolled in the French national multicentre prospective observational cohort study, with cord blood samples available for a subset of deliveries (n = 9). Following model evaluation, maternal plasma profiles and fetal exposure trajectories were simulated across gestation.
Results: The integrated pregnancy PBPK models robustly captured maternal and fetal ETI concentration-time profiles, with the majority of observations falling within the 5th–95th percentile prediction intervals. Simulations predicted a progressive decrease in maternal systemic exposure during pregnancy, reaching up to 58.3% 60.4% and 66.2% for elexacaftor, tezacaftor, and ivacaftor, respectively, by the end of the third trimester. Cord blood–to–maternal plasma area-under-the-curve (AUC) ratios were calculated over 24 hours for elexacaftor and tezacaftor and over 12 hours for ivacaftor. In late gestation, predicted cord blood-to-maternal plasma AUC ratios were 0.64 for elexacaftor, 0.65 for tezacaftor, and 0.48 for ivacaftor.
Conclusions: By integrating empirical ex vivo placental data with real-world clinical pharmacokinetics, this study provides a mechanistically informed prediction of ETI disposition in pregnancy. The model provides a quantitative framework to characterize maternal and fetal exposure across gestation, addressing a critical clinical knowledge gap in the management of pregnant women with CF. This approach supports model-informed evaluation of ETI dosing strategies during pregnancy and offers a translational platform for balancing maternal therapeutic efficacy with fetal exposure considerations in an increasingly prevalent clinical context.
References:
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6. Taylor-Cousar JL, Jain R. Maternal and fetal outcomes following elexacaftor-tezacaftor-ivacaftor use during pregnancy and lactation. Journal of Cystic Fibrosis. 2021 May;20(3):402–6. doi:10.1016/j.jcf.2021.03.006
7. Metcalf A, Martiniano SL, Sagel SD, Zaretsky MV, Zemanick ET, Hoppe JE. Outcomes of prenatal use of elexacaftor/tezacaftor/ivacaftor in carrier mothers to treat meconium ileus in fetuses with cystic fibrosis. J Cyst Fibros. 2025 May;24(3):466–8. doi:10.1016/j.jcf.2024.11.011 PubMed PMID: 39645477.
Reference: PAGE 34 (2026) Abstr 12126 [www.page-meeting.org/?abstract=12126]
Poster: Drug/Disease Modelling - Absorption & PBPK