Abstract
Aim: The number of pregnancies among women with cystic fibrosis (wwCF) has steadily increased over the past decade. However, the pharmacokinetics (PK) of elexacaftor-tezacaftor-ivacaftor (ETI) during gestation remains uncharacterized, despite its widespread use in this population. To date, no clinical trials have investigated the effectiveness, safety or PK profiles of ETI during pregnancy. Given the significant physiological changes that occur throughout gestation, which can alter drug PK, characterizing how pregnancy impacts ETI exposure represents a key step towards informing appropriate dosing strategies. Therefore, the aim of this analysis was to assess pregnancy effect on ETI PK.
Method: As part of the French national observational cohort study, therapeutic drug monitoring was performed in 145 wwCF, including 14 pregnant participants. PK profiles for each compound were characterized using the previously published ETI adult population PK model from the same cohort, with model development and evaluation performed using Monolix® software.
Results: A total of 294 plasma samples, including 47 collected from pregnant participants, were drawn during routine clinical care. Pregnancy was found to significantly increase the apparent clearance of tezacaftor (0.97 to 1.44 L/h) and of ivacaftor (9.64 to 11.36 L/h), indicating a decrease in systemic exposure.
Conclusion: These findings raise important questions regarding whether decreased total tezacaftor and ivacaftor exposure may compromise the sustained treatment efficacy. The necessity for dose adjustments during pregnancy remains to be evaluated from a PK (unbound ETI concentrations) and pharmacodynamic (clinical effectiveness) perspective, thus warranting further studies.
Keywords: cystic fibrosis; elexacaftor–tezacaftor–ivacaftor; population pharmacokinetics; pregnancy.