Therapeutic drug monitoring of elexacaftor, tezacaftor, and ivacaftor before, during, and after pregnancy in women with cystic fibrosis: An observational study.

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) has improved health and increased life expectancy in many patients with cystic fibrosis (pwCF). Family planning issues have become more important since then. Many women decide to remain on modulator therapy during pregnancy despite insufficient evidence-based recommendations for continuing ETI during pregnancy and lactation.

Methods: In this retrospective observational report, we present data on maternal serum concentrations of ETI, assessed via a therapeutic drug monitoring (TDM) program established at our CF center for adults. Blood was taken during routine visits. We retrospectively analyzed the corresponding predicted forced expiratory volume in 1 s (ppFEV), at five time points before, during, and after pregnancy.

Results: Of seven ETI-exposed pregnancies in six women between February 2021 and September 2023, the intake of ETI resulted in no maternal complications and healthy offspring. The dose was reduced in all women, 71.4 % before and 28.6 % during pregnancy, primarily as a result of side effects and/or increased ETI concentrations. Despite dose reductions, serum concentrations showed a broad distribution, with values below, within, and above the C range according to the pharmacokinetic data in the manufacturer's product characteristics. Pulmonary function largely remained stable without pulmonary exacerbations requiring intravenous antibiotic treatment.

Conclusion: This observational report shows the most extensive dataset for ETI concentrations during pregnancy. Individualized dose adjustments could help to resolve adverse side effects while continuing CFTR therapy. Specific populations, such as pregnant women, might benefit from a TDM. However, future research with more pharmacokinetic data from pregnant pwCF is needed.