Effect of polymorphic variants of genes involved in the phase I genes of xenobiotic biotransformation on the effectiveness and safety of therapy with CFTR modulators in cystic fibrosis with and without complications

   Polymorphism of genes involved in drug metabolism is one of the most common inherited risk factors associated with adverse drug reactions.

   The aim of the study was to study the effect of the polymorphism of genes involved in the phase 1 of xenobiotic biotransformation on the efficacy and safety of CFTR modulator therapy in cystic fibrosis, taking into account the complications, in order to optimize therapy.

   Methods. The study included 301 patients with the average age of 11.1 ± 3.8 years who received lumacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor in 2022–2024. Gene polymorphism was investigated for the following enzymes involved in the phase I of the drug metabolism: CYP2C9*3 (rs1057910; c.1075A>C; I359L), CYP2C9*2 (rs1799853; c.430 C>T; R144C), CYP2C19*2 (rs4244285; c.681G>A), CYP2C19*3 (rs4244285; c.681G>A), (rs4986893; c.636G>A; W212X), CYP2D6*4 (rs3892097; 1846G>A), CYP3A4*3 (rs4986910; M445T; c.1334 T>C), and CYP3A4*1B (rs2740574; c.-392C>T). The study was performed by PCR followed by RFLP analysis (restriction fragment length polymorphism) or AFLP analysis (amplified fragment length polymorphism).

   Results. Patients with the GG genotype of the CYP2D6*4 polymorphic variant of the CYP2D6 gene showed better weight gain after one year of therapy with CFTR modulators (p = 0.048). Patients with the AC genotype of the CYP2C9*3 polymorphic variant of the CYP2C9 gene demonstrated higher weight, height, and BMI before and one year after the therapy (p < 0.05), as well as better height gain over time (p = 0.010) compared to the carriers of the AA genotype, which indicates a higher efficacy of the targeted therapy in the AC genotype carriers. Patients with the GG genotype of the CYP2D6*4 polymorphic variant of the CYP2D6 gene and the AA genotype of the CYP2C19*2 polymorphic variant of the CYP2C19 gene more often had side effects and elevated serum liver transaminases. Patients with cirrhosis were more likely to have elevated transaminases and adverse events during the targeted therapy compared to the patients without any liver disease. Patients with a history of meconium ileus had lower FVC values after one year of therapy, higher ALT before/after therapy, and higher AST after therapy, and also showed better annual height gain during CFTR modulator therapy (p < 0.05).

   Conclusion. Determination of the genotype of polymorphisms CYP2C9*3 of the CYP2C9 gene, CYP2C19*2 of the CYP2C19 gene, and CYP2D6*4 of the CYP2D6 gene may be important for predicting the efficacy and safety (toxic effects on the liver) of targeted therapy for cystic fibrosis.

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