Entry of cystic fibrosis transmembrane conductance potentiator ivacaftor into the developing brain and lung.

BACKGROUND

The potential effects of ivacaftor during pregnancy and breastfeeding on the offspring are still unknown. This study aimed to investigate pre-/postnatal age-related entry into the brain and lungs and transfer of maternally administered drug by the placental and via the milk.

METHODS

In acute experiments Sprague Dawley rats at embryonic day (E) 19, postnatal days (P) 4, 9, 16, and adult were administered an intraperitoneal injection of ivacaftor (40 mg/kg) traced with [3H] ivacaftor. To determine tissue entry, plasma, cerebrospinal fluid (CSF), lungs and brains were collected, and radioactivity measured using liquid scintillation counting. For long term experiments pregnant dams were orally treated at 25 mg/kg/day for 7 days and pups collected at E19. For postnatal pups, dams received treatment for 7 or 14 days and pups were collected at P6, 9, 13 and 16. To estimate placental and milk transfer concentration of ivacaftor in pup & maternal plasma was determined by liquid chromatography-mass spectrometry.

RESULTS

At all ages, entry of ivacaftor into lungs, following either acute or prolonged exposure, was much higher than into brain & CSF. Brain entry appeared higher at earlier ages. Transfer across the placenta and breast milk. was estimated to be around ~40% of maternal plasma.

CONCLUSIONS

Fetal and postnatal rats were exposed to maternally administered ivacaftor via placental and milk transfer. Preferential entry in the lungs at all ages suggests the possibility that exposing CF babies to maternally administered ivacaftor could be beneficial for limiting progression of CF pathology in early development.