Predicting Maternal and Fetal Exposures of Elexacaftor-Tezacaftor-Ivacaftor during Pregnancy through Physiologically Based Pharmacokinetic Models.

The use of elexacaftor/tezacaftor/ivacaftor (ETI) has been associated with increased fertility in women with cystic fibrosis (CF) and is increasingly used during pregnancy to support both maternal and fetal health. However, little is known about the pharmacokinetics (PK) of ETI during pregnancy, which is crucial for optimizing its efficacy and safety. This study aimed to predict the PK of ETI during pregnancy and to determine the maternal dose required to achieve therapeutic concentrations in both the maternal and fetus. The pregnancy physiological-based pharmacokinetic (PBPK) model within the Simcyp Simulator was used to predict the maternal and feto-placental exposure of ETI. Placental kinetics were parameterized using permeability parameters determined from the physicochemical properties of these compounds. The model closely predicted the observed data, with the observed ETI maternal plasma concentrations, cord concentrations, and infant plasma concentrations mostly falling within the range of predicted 5th to 95th percentiles. Steady-state simulations up to gestational week 40 predicted a continuous decline in ETI concentrations, with the AUC declining to 32.4-37.5% of baseline levels by week 40. However, the 5th percentile of trough concentrations for ETI consistently remained above the efficacy thresholds, both in mother and fetus. Therefore, it appears reasonable to maintain standard dosing regimen during pregnancy, complemented by careful monitoring. A clinical trial, such as the ongoing Maternal and Fetal Outcomes in the Era of Modulators (MAYFLOWERS) study, is required to further confirm the efficacy and safety of ETI in this population.