Scholarlink

Background and Objectives <p>Elexacaftor–tezacaftor–ivacaftor (ETI), a combination of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, has become the therapeutic standard of care for most people with cystic fibrosis (pwCF). People with cystic fibrosis exhibit differences in CFTR genotypes and have important differences in phenotypic characteristics including age, body weight, pancreatic status, disease severity, and comorbidities. While these differences predict large interindividual variability (IIV) in ETI exposure, there is a unique dose regimen recommended for adults. This raises questions around the “one-dose fits all” strategy.</p> Objectives <p>The aims of this study were to describe real-world population pharmacokinetics (Pop-PK) of ETI in adults with CF and identify factors associated with IIV.</p> Method <p>As part of the ongoing French national observational cohort study the Pop-PK analysis included 552 plasma concentrations drawn routinely from 325 adults with CF.</p> Results <p>A one-compartment model with first order absorption and elimination best represented all three compounds, and an additional lag-time for elexacaftor PK data. Large IIV was observed in ETI, with an area under the curve (AUC<sub>0–24h</sub> for elexacaftor and tezacaftor, and AUC<sub>0–12h</sub> for ivacaftor) ranging respectively, from 58.7–422.9 mg⋅h/L; 38.0–207.7 mg⋅h/L and 4.9–64.9 mg⋅h/L. The main sources of IIV identified in the final ETI Pop-PK models were body weight, age, exocrine pancreatic insufficiency and <i>CFTR</i> genotype.</p> Conclusion <p>This study established the first ETI Pop-PK analysis in adults with CF and identified several covariates that explain IIV. Therapeutic drug monitoring may be beneficial for patients with a small body weight, older ages, carrying one ETI-responsive <i>CFTR</i> variant or those with no exocrine pancreatic insufficiency and especially for patients who combine these characteristics. Therapeutic drug monitoring may also prove to be useful in individuals experiencing adverse events, in those with reduced effectiveness, or to help manage non-adherence issues.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Population Pharmacokinetics of Elexacaftor, Tezacaftor and Ivacaftor in a Real-World Cohort of Adults with Cystic Fibrosis

  • 期刊论文

  • 发表日期：

    2025年5月22日

查看全文
  • Paulette Magnas,
  • Naïm Bouazza,
  • Frantz Foissac,
  • Léo Froelicher Bournaud,
  • Gabrielle Lui,
  • Nicolas Carlier,
  • Jennifer Da Silva,
  • Johanna Fesenbeckh,
  • Reem Kanaan,
  • Isabelle Honoré,
  • Clémence Martin,
  • Jean-Marc Treluyer,
  • Pierre-Régis Burgel,
  • Sihem Benaboud

摘要

Background and Objectives

Elexacaftor–tezacaftor–ivacaftor (ETI), a combination of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, has become the therapeutic standard of care for most people with cystic fibrosis (pwCF). People with cystic fibrosis exhibit differences in CFTR genotypes and have important differences in phenotypic characteristics including age, body weight, pancreatic status, disease severity, and comorbidities. While these differences predict large interindividual variability (IIV) in ETI exposure, there is a unique dose regimen recommended for adults. This raises questions around the “one-dose fits all” strategy.

Objectives

The aims of this study were to describe real-world population pharmacokinetics (Pop-PK) of ETI in adults with CF and identify factors associated with IIV.

Method

As part of the ongoing French national observational cohort study the Pop-PK analysis included 552 plasma concentrations drawn routinely from 325 adults with CF.

Results

A one-compartment model with first order absorption and elimination best represented all three compounds, and an additional lag-time for elexacaftor PK data. Large IIV was observed in ETI, with an area under the curve (AUC0–24h for elexacaftor and tezacaftor, and AUC0–12h for ivacaftor) ranging respectively, from 58.7–422.9 mg⋅h/L; 38.0–207.7 mg⋅h/L and 4.9–64.9 mg⋅h/L. The main sources of IIV identified in the final ETI Pop-PK models were body weight, age, exocrine pancreatic insufficiency and CFTR genotype.

Conclusion

This study established the first ETI Pop-PK analysis in adults with CF and identified several covariates that explain IIV. Therapeutic drug monitoring may be beneficial for patients with a small body weight, older ages, carrying one ETI-responsive CFTR variant or those with no exocrine pancreatic insufficiency and especially for patients who combine these characteristics. Therapeutic drug monitoring may also prove to be useful in individuals experiencing adverse events, in those with reduced effectiveness, or to help manage non-adherence issues.