Maternal, newborn and breast milk concentrations of elexacaftor/tezacaftor/ivacaftor in a F508del heterozygous woman with cystic fibrosis following successful pregnancy

Abstract

With the introduction of elexacaftor/tezacaftor/ivacaftor (ETI), more women with cystic fibrosis (CF) are likely to grow families. Hence, an understanding long-term safety and effects of CFTR modulators on fertile women and children while monitoring their concentrations is crucial. Here, we report on the development of an improved LC-MS/MS methodology to measure ETI concentrations in maternal and child blood and breastmilk, applied in one case of successful pregnancy of a 30-year-old woman with CF (F508del/R334W). We observed that ETI remains stable in breastmilk, is absorbed by the infant and can be detected in child plasma. Our results confirm accumulating evidence of a successful pregnancy in women treated with CFTR modulators without significant side effects on the child and provide valuable analytical procedures suitable for the post-marketing evaluation of CFTR modulators in pregnant and lactating women, as well as in their infants.

Keywords: CFTR modulator therapy; F508del CFTR; R334W CFTR; drug monitoring; mass spectrometry; novel therapies; pregnancy.

Figure 1

LC–MS/MS method development for measuring ETI in biological samples. (A,B) HPLC chromatograms of VX-445, VX-661, and VX-770 spiked (0.05 ng/μL) in pooled blank human plasma or breastmilk. Proteins were removed by precipitation and samples injected (10 μL) into the C18-HPLC system. (C–E) Full product ion scan plots of VX-455, VX-661, and VX-770 obtained with MS/MS. Main transitions for each target molecules are in red. Bond cleavage sites are represented by dashed lines. Data are representative from n = 20 LC–MS/MS separate injections.

Figure 2

Mean calibration curves of ETI in human plasma and breast milk. Eight-point calibration curves were obtained for each an-analyte with a pool of blank plasma and/ milk spiked with 0.39–50 pg./μL of working solutions of VX-445, VX-661, and VX-770. Relative responses were calculated as ratio between area of the standard (n = 5 replicate/concentration) over that of IS.