A descriptive case series of hepatotoxicity associated with CFTR modulators and possible relevance of pharmacogenetic polymorphisms in cystic fibrosis patients.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are widely used in patients with cystic fibrosis and significantly improve respiratory function and quality of life. However, their effectiveness may be limited by liver damage, which sometimes leads to treatment discontinuation, and the mechanisms underlying this remain poorly understood. This case series explores the role of genetic polymorphisms affecting the enzymes and transporters involved in their pharmacokinetics, as well as detoxification mechanisms (CYP3A4/CYP3A5/ABCB1/SLCO1B1/GSTP1/GSTM1/GSTT1). Six cases of hepatotoxicity under CFTR modulators were assessed using the RECAM score. Among the genetic polymorphisms assessed, CYP3A4*22 (rs35599367) allele had higher allele frequency than in the European population, which usually does not express CYP3A5. This genetic variant, reducing CYP3A activity, could decrease the elimination of CFTR modulators and increase the risk of liver toxicity. Other genetic factors may also be involved. Further studies are needed to confirm these results.