PI-088 - POPULATION PHARMACOKINETICS OF ELEXACAFTOR, TEZACAFTOR AND IVACAFTOR IN REAL WORLD ADULT PATIENTS WITH CYSTIC FIBROSIS
Wednesday, May 28, 2025
5:00 PM - 6:30 PM East Coast USA Time
P. Magnas1, N. BOUAZZA2, F. Foissac3, L. Froelicher Bournaud4, G. Lui5, J. Treluyer6, P. Burgel7, S. Benaboud8; 1URP 7323, Cochin Hospital, Paris Cité University, Paris, France, 2URP7323 & Unité de Recherche Clinique, Université Paris Cité Necker/Cochin, Tarnier Hospital, Paris, France, 3URP7323 & Unité de Rechernche Clinique, Université Paris Cité Necker/Cochin, Tarnier Hospital, Paris, France, 4URP 7323 & Service de Pharmacologie Clinique, Cochin Hospital, AP-HP, Groupe Hospitalier Paris Centre,, Paris, France, 5URP 7323, Cochin Hospital & CIC-1419 Inserm, Cochin-Necker Hospital, Paris, France, 6Service de Pharmacologie Clinique, Hôpital Cochin & HEGP, AP-HP, Groupe Hospitalier Paris Centre, Paris, France, 7Service de Pneumologie, CHU de Cochin, AP-HP, Inserm U1016, Paris, France, 8URP 7323, Service de Pharmacologie Clinique, Cochin Hospital, AP-HP, Groupe Hospitalier Paris Centre, Paris, France.
PhD student URP 7323, Cochin Hospital, Paris Cité University Paris, Ile-de-France, France
Background: The use of Elexacaftor-Tezacaftor-Ivacaftor (ETI), a combination of CFTR modulators, has become the therapeutic standard of care for patients with cystic fibrosis (pwCF). However, cystic fibrosis (CF) patient profiles may vary drastically between individuals, with age, weight, disease severity, comorbidities or genotype. While large inter-individual variability (IIV) in ETI exposure is expected, there is a unique dose regimen recommended for adults. This raises questions around the “one-dose fits all” strategy and urges for the rational development of a population pharmacokinetic (POP-PK) model and perhaps a therapeutic drug monitoring (TDM) strategy. These tools should help in dose optimization especially in patients that don’t present clinical improvements or show side effects. To the best of our knowledge, no real-world POP-PK models have been developed for ETI in adult pwCF. Methods: As part of the ongoing French national observational cohort study, we aimed to describe a POP-PK model of ETI, using nonlinear mixed-effect modeling. By such, we characterized the pharmacokinetics (PK) of each compound in adult pwCF and identified factors associated with IIV. Simulations were conducted, using the R software, to predict ETI PK according to the different covariates identified in the final POP-PK models and to further narrow down the sensitive populations that could be recommended for TDM. The POP-PK analysis included over 500 plasma concentrations drawn routinely from 326 adult pwCF. Results: A one-compartment model with first order absorption and elimination best represented all three compounds, and with an additional lag-time for Elexacaftor PK data. A large IIV was observed in ETI, with an area under the curve (AUC0-24h for Elexacaftor and Tezacaftor, and AUC0-12h for Ivacaftor) ranging respectively, from 58.7 – 435.8 mg.h/L; 38.20 – 203.60 mg.h/L and 0.09 – 4.93 mg.h/L. The main sources of IIV that were identified, were patient’s bodyweight, age, exocrine pancreatic insufficiency and patient’s genotype. Conclusion: This study is the first ETI POP-PK analysis in adult pwCF. We identified factors that explain IIV and thus, determine sub-groups of CF populations that could benefit from TDM. The use of TDM and POP-PK models as a basis for dose adjustment in adult pwCF may be useful.