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.

中文翻译：

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囊性纤维化跨膜电导增强剂ivacaftor进入发育中的脑和肺

背景

ivacaftor 在怀孕和哺乳期间对后代的潜在影响仍然未知。本研究旨在调查与出生前/出生后年龄相关的进入大脑和肺部的情况以及母体给药的药物通过胎盘和乳汁的转移。

方法

在急性实验中，Sprague Dawley 大鼠在胚胎第 (E) 19 天、产后第 (P) 4、9、16 天和成人腹膜内注射 ivacaftor (40 mg/kg)，用 [3H] ivacaftor 示踪。为了确定组织进入，收集血浆、脑脊液 (CSF)、肺和脑，并使用液体闪烁计数测量放射性。对于长期实验，怀孕的水坝以 25 mg/kg/天的剂量口服治疗 7 天，并在 E19 收集幼崽。对于产后幼崽，母鼠接受治疗 7 或 14 天，并在 P6、9、13 和 16 收集幼崽。通过液相色谱-质谱法测定幼崽和母体血浆中依伐卡托的胎盘和乳汁转移浓度。

结果

在所有年龄段，在急性或长期暴露后，ivacaftor 进入肺部的比例远高于进入脑和脑脊液。在早期，大脑进入率更高。通过胎盘和母乳转移。估计约为母体血浆的 40%。

结论

胎儿和产后大鼠通过胎盘和乳汁转移暴露于母体给予的ivacaftor。在所有年龄优先进入肺部表明，将 CF 婴儿暴露于母体给予的ivacaftor 可能有利于限制早期发育中 CF 病理学的进展。