The relationship between the pharmacogenetics and pharmacokinetics of CFTR modulators in a population of children with cystic fibrosis

The triple combination of elexacaftor / tezacaftor / ivacaftor is one of the key tools for targeted pharmacotherapy of cystic fibrosis. In the pediatric population, its use may be accompanied by a variable therapeutic response, which may be due to age-related pharmacokinetic features, as well as the influence of genetic polymorphism of biotransformation enzymes.

The aim. To analyze the pharmacokinetic parameters of elexacaftor, tezacaftor, ivacaftor, and lumacaftor in patients with cystic fibrosis, and to study the influence of various polymorphisms of cytochrome P450 genes (CYP2C6*4, CYP2C19*2, CYP2D6*4) and the UGT1A1 gene on pharmacokinetics.

Materials and Methods. The prospective single-center study included 32 patients with cystic fibrosis aged 6 to 18 years, of whom 29 received the combination of elexacaftor / tezacaftor / ivacaftor, and 3 received the dual combination of ivacaftor / lumacaftor. Analyte concentrations in plasma were determined by HPLC-MS/MS at five time points within 12 hours after drug administration. Molecular genetic analysis was performed on total DNA isolated from whole blood leukocytes using the phenol-chloroform extraction method.Results. Significant inter-individual variability in the pharmacokinetic parameters of all studied CFTR modulators was revealed. Normalized maximum concentrations of elexacaftor and ivacaftor were significantly higher in patients aged ≥ 12 years (p = 0.027 and p = 0.046, respectively). Carriage of the CYP2C9*4 (GG) genotype, associated with slow metabolism, led to a statistically significant increase in the systemic exposure of elexacaftor (p = 0.007) and ivacaftor (p = 0.034). For the CYP2D6*4 (AA) genotype, a significant increase in elexacaftor concentration 3 hours after administration was found (p = 0.041). Polymorphism of the UGT1A1 gene, including genotypes associated with Gilbert’s syndrome, did not have a significant effect on the total exposure of the studied drugs, while lower concentrations of tezacaftor and elexacaftor were noted at individual time points in carriers of the *28 allele.

Conclusion. The pharmacokinetics of CFTR modulators in children are characterized by high variability and depend on age and the polymorphism of genes encoding CYP2C9 and CYP2D6 isoenzymes. The obtained data justify the need for further research to optimize dosing, taking into account genetic and demographic factors.

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