Understanding CFTR Functionality: A Comprehensive Review of Tests and Modulator Therapy in Cystic Fibrosis.

Cystic fibrosis is a genetic disorder inherited in an autosomal recessive manner. It is caused by a mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene on chromosome 7, which leads to abnormal regulation of chloride and bicarbonate ions in cells that line organs like the lungs and pancreas. The CFTR protein plays a crucial role in regulating chloride ion flow, and its absence or malfunction causes the production of thick mucus that affects several organs. There are more than 2000 identified mutations that are classified into seven categories based on their dysfunction mechanisms. In this article, we have conducted a thorough examination and consolidation of the diverse array of tests essential for the quantification of CFTR functionality. Furthermore, we have engaged in a comprehensive discourse regarding the recent advancements in CFTR modulator therapy, a pivotal approach utilized for the management of cystic fibrosis, alongside its concomitant relevance in evaluating CFTR functionality.

Cystic Fibrosis: Highly Effective Targeted Therapeutics and the Impact on Sex and Racial Disparities.

People with Cystic Fibrosis (CF) are living longer and healthier lives due in part to new therapies, called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators. However, disparities in outcomes still exist, with females demonstrating a shorter life expectancy than males; this is opposed to the typical female versus male life expectancy in the general United States population. In addition, minority populations such as those of Hispanic ethnicity and African Americans are less frequently eligible for these new CFTR modulators. The mechanisms driving this difference and the relative contribution of CFTR to the etiology are not yet elucidated.

Isotope dilution LC-MS/MS quantification of the cystic fibrosis transmembrane conductance regulator (CFTR) modulators ivacaftor, lumacaftor, tezacaftor, elexacaftor, and their major metabolites in human serum.

OBJECTIVES: Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators have revolutionized the therapeutic landscape in CF treatment. These vital drugs are extensively metabolized via CYP3A, so caution must be exercised in multimodal CF therapy because of the risk of adverse drug interactions. Our goal was to develop a highly sensitive assay for the purpose of therapeutic drug monitoring (TDM) in diagnostic laboratories. METHODS: After protein precipitation, the CFTR modulators ivacaftor, lumacaftor, tezacaftor, elexacaftor, and their metabolites ivacaftor-M1, ivacaftor-M6, and tezacaftor-M1 were separated with a two-dimensional chromatography setup within 5 min, and quantified with stable isotope-labeled internal standards. The method was validated according to the European Medicines Agency (EMA) guideline on bioanalytical method validation and applied to CF patient samples. RESULTS: Inaccuracy was ≤7.0% and the imprecision coefficient of variation (CV) was ≤8.3% for all quality controls (QCs). The method consistently compensated for matrix effects, recovery, and process efficiency were 105-115 and 96.5-103%, respectively. Analysis of CF serum samples provided concentrations comparable to the pharmacokinetic profile data reported in the EMA assessment report for the triple combination therapy Kaftrio. CONCLUSIONS: We hereby present a robust and highly selective isotope dilution liquid chromatography tandem mass spectrometry (ID-LC-MS/MS) assay for the simultaneous quantification of the so far approved CFTR modulators and their metabolites in human serum. The assay is suitable for state-of-the-art pharmacovigilance of CFTR modulator therapy in CF patients, in order to maximize safety and efficacy, and also to establish dose-response relationships in clinical trials.

Using Negative Control Outcomes and Difference-in-Differences Analysis to Estimate Treatment Effects in an Entirely Treated Cohort: The Effect of Ivacaftor in Cystic Fibrosis.

When an entire cohort of patients receives a treatment, it is difficult to estimate the treatment effect in the treated because there are no directly comparable untreated patients. Attempts can be made to find a suitable control group (e.g., historical controls), but underlying differences between the treated and untreated can result in bias. Here we show how negative control outcomes combined with difference-in-differences analysis can be used to assess bias in treatment effect estimates and obtain unbiased estimates under certain assumptions. Causal diagrams and potential outcomes are used to explain the methods and assumptions. We apply the methods to UK Cystic Fibrosis Registry data to investigate the effect of ivacaftor, introduced in 2012 for a subset of the cystic fibrosis population with a particular genotype, on lung function and annual rate (days/year) of receiving intravenous (IV) antibiotics (i.e., IV days). We consider 2 negative control outcomes: outcomes measured in the pre-ivacaftor period and outcomes among persons ineligible for ivacaftor because of their genotype. Ivacaftor was found to improve lung function in year 1 (an approximately 6.5-percentage-point increase in ppFEV1), was associated with reduced lung function decline (an approximately 0.5-percentage-point decrease in annual ppFEV1 decline, though confidence intervals included 0), and reduced the annual rate of IV days (approximately 60% over 3 years).

Optimising the care and quality of life of people with cystic fibrosis: the influence of cystic fibrosis transmembrane conductance regulator modulators.

Cystic fibrosis is a life-limiting, inherited, multi-organ disease which affects many systems of the body. Until recently, treatments were only able to ameliorate symptoms, but the introduction of precision medications which modulate the underlying defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene has changed this. Notably improvements in nutrition and lung function, reduced use of antibiotics and reduced occupation rates for hospital beds have been seen. This article summarises the discussion of a group of healthcare professionals from different specialties and an expert patient, representing their personal views and experience of treating patients who are using CFTR modulators. The discussion was sponsored by an unrestricted grant from Chiesi Limited (Manchester, UK).