Evaluating Maternal and Neonatal Pharmacokinetics of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulators - The ELECTRA Pregnancy Study - ABSTRACT Cystic fibrosis (CF) is a devastating multi-organ system disease that results in lifelong morbidity and early mortality. Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators (elexacaftor/tezacaftor/ivacaftor) have revolutionized CF patient care, restoring normal function to people with CF (pwCF) who respond. Their use also tripled pregnancy rates in pwCF, a population where subfertility and maternal complications exist at a significantly higher rate. Pregnant women with CF have an increased risk of infection, requiring prolonged hospitalizations for intravenous antibiotics and other complications, including pulmonary decline. Consequently, they are advised to continue CFTR modulator therapy to prevent maternal deterioration, despite the lack of scientific evidence demonstrating their optimal dosing in pregnancy. As such, it is critical to define the pharmacokinetics of CFTR modulators in pregnancy and postpartum, including effects on the developing fetus, the infant, and breastmilk composition. Former NIH Director, Dr. Francis Collins, highlighted critical knowledge gaps in the pharmacology of modulator drugs, and in 2022 the NIH reaffirmed these gaps to include optimal dosing, pharmacology, and use in pregnancy and lactation. Our research group’s ongoing studies with the triple combination (TC) therapy (elexacaftor/tezacaftor/ivacaftor) in the adult CF population reveal substantial inter-individual variation in the concentrations of these compounds that can affect response. Previous attempts to define the pharmacokinetics of CFTR modulators in postpartum patients have been unsuccessful due to difficulties with recruitment and retention. To address this challenge, we have identified seven geographically diverse clinical research centers across the U.S. with exceptional recruitment and retention records in both the Cystic Fibrosis Foundation/Therapeutic Development Network and the NIH/NICHD Maternal-Fetal Medicine Units Network. Led by a team of Cystic Fibrosis and Maternal-Fetal Medicine investigators, we will enroll 30 pregnant, first- trimester, patients on TC to investigate the following aims: 1) To determine the pharmacokinetics of each compound in CFTR modulator therapy, including active metabolites, in pregnant individuals in each trimester and postpartum, and 2) To evaluate the wash-out pharmacokinetics of each compound in CFTR modulator therapy, including active metabolites, from newborns of mothers taking TC. The ELECTRA Pregnancy Study is poised to generate rigorous CFTR Modulator pharmacokinetic data to inform optimal CFTR Modulator dosing to improve outcomes for pregnant patients with cystic fibrosis and their infants.
