Pharmacokinetic assessment of elexacaftor/tezacaftor/ivacaftor and their metabolites in maternal blood, cord blood, the neonate, and breastmilk of a cystic fibrosis carrier mother/affected fetus dyad

Abstract

There are a paucity of data regarding the pharmacokinetics (PK) of elexacaftor (ELX)/tezacaftor(TEZ)/ivacaftor(IVA)(ETI) in pregnant and/or lactating mothers and their offspring. We conducted a PK assessment of ETI and their metabolites in maternal/neonatal/cord blood and breast milk from a cystic fibrosis (CF) carrier mother/affected fetus dyad, collecting specimens at delivery, 1 and 4 weeks after birth. The infant received on-label direct dosing after 1 month of life; all PK samples were collected prior to initiation of neonatal dosing and analyzed using LC-MS/MS. Measured metabolites were IVA-M1, IVA-M6, ELX-M23 and TEZ-M1. The female infant was born at 37 weeks gestation with successful meconium passage on the first day of life. Sweat chloride at 15 days (16 and 17 mmol/L) and immunoreactive trypsinogen (27.5 ng/mL) were normal. Neonatal genetics confirmed F508del/P67L genotype. Parent drug concentrations were measurable in cord blood and capillary heel sticks, indicating they cross the placenta. After delivery, the infant's only source of modulators was via breast milk. Breast milk concentrations were measured at 1 and 4 weeks of life. Relative to maternal concentrations, ETI and their metabolites were present at lower concentrations. Heel stick specimens revealed undetectable IVA, but ELX and TEZ were below the assay limit. IVA-M1 and IV-M6 concentrations were lower at 1 and 4 weeks relative to delivery. To our knowledge, this is the first report of ETI metabolite concentrations following in utero administration.

Keywords: Cystic fibrosis; In utero therapy; Pregnancy.