Therapeutic Drug Monitoring of Ivacaftor, Lumacaftor, Tezacaftor, and Elexacaftor in Cystic Fibrosis: Where Are We Now?
Ontology highlight
ABSTRACT:
SUBMITTER: Choong E
PROVIDER: S-EPMC9412421 | biostudies-literature | 2022 Aug
REPOSITORIES: biostudies-literature
Publications
Therapeutic Drug Monitoring of Ivacaftor, Lumacaftor, Tezacaftor, and Elexacaftor in Cystic Fibrosis: Where Are We Now?
Choong Eva E Sauty Alain A Koutsokera Angela A Blanchon Sylvain S André Pascal P Decosterd Laurent L
Pharmaceutics 20220811 8
Drugs modulating the cystic fibrosis transmembrane conductance regulator (CFTR) protein, namely ivacaftor, lumacaftor, tezacaftor, and elexacaftor, are currently revolutionizing the management of patients with cystic fibrosis (CF), particularly those with at least one <i>F508del</i> variant (up to 85% of patients). These "caftor" drugs are mainly metabolized by cytochromes P450 3A, whose enzymatic activity is influenced by environmental factors, and are sensitive to inhibition and induction. Hen ...[more]
Similar Datasets
Project description:Background/objectivesElexacaftor, tezacaftor, and ivacaftor (ETI) have significantly improved lung function in people with cystic fibrosis (pwCF). Despite exceptional improvements in most cases, treatment-related inter-subject variability and drug-drug interactions that complicate modulator therapy have been reported.MethodsThis retrospective analysis presents data on the serum concentration of ETI in our pwCF with full or reduced dosage from August 2021 to December 2023 via routine therapeutic drug monitoring (TDM). The data were compared with the maximum drug concentrations (Cmax) from the pharmaceutical company's summary of product characteristics.ResultsA total of 786 blood samples from 155 pwCF (41% female, 59% male) were analyzed. The examinations were divided into four groups: full dose within the given tmax (38.5% of all measurements), full dose outside the tmax (29%), reduced dose within the tmax (19.2%), and reduced dose outside the tmax (13.2%). In pwCF receiving the full dose and blood taken within the tmax, 45.3% of serum concentrations of elexacaftor, 51.1% of serum concentrations of ivacaftor, and 8.9% of serum concentrations of tezacaftor were found to be above the Cmax, respectively. For those on reduced doses within the tmax, 24.5% had a serum concentration of elexacaftor, 23.2% had a serum concentration of ivacaftor, and 2.5% had a serum concentration of tezacaftor above the Cmax, respectively.ConclusionsMany pwCF under ETI therapy have Cmax values for elexacaftor and ivacaftor above the recommended range, even on reduced doses or before the tmax was reached. This highlights the value of a TDM program. Further pharmacokinetic studies are necessary.
| S-EPMC11508966 | biostudies-literature
Project description:BackgroundMany individuals with cystic fibrosis (CF) have chronic rhinosinusitis resulting in nasal obstruction, sinus infections, and repeated surgeries. Elexacaftor-tezacaftor-ivacaftor is a highly effective modulator therapy approved for individuals aged 6 years or older with CF who have at least one F508del allele or other responsive mutation. The current study tests the hypothesis that ELX/TEZ/IVA improves sinonasal disease in CF.MethodsThe study was a pre/post, observational cohort study conducted at two sites. Participants underwent a study visit prior to starting ELX/TEZ/IVA and a second visit at a median of 9 months on therapy. Each visit included sinus CT scan, rigid nasal endoscopy, and sweat chloride measurement. Symptoms were measured with the 22 item Sinonasal Outcome Test at scheduled intervals during the study. Regression models were used to test for improvement in symptoms, endoscopy, and CT scales.ResultsThe study enrolled 34 individuals, with a median age of 27 years (range 12-60). Symptoms improved within 7 days of therapy and plateaued by day 28. Endoscopic crusting resolved and nasal polyposis improved, with a decrease in size or resolution of polyps. Sinus opacification and mucosal thickening improved on CT radiographs with treatment.ConclusionsSinonasal symptoms improved rapidly and durably for at least 180 days on ELX/TEZ/IVA therapy. Objective measures of disease including endoscopic and CT findings improved with ELX/TEZ/IVA.
| S-EPMC9470769 | biostudies-literature
Project description:BackgroundCystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes.MethodsWe conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes. Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV1) at week 4.ResultsA total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor-tezacaftor-ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor-tezacaftor-ivacaftor group.ConclusionsElexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.).
| S-EPMC7282384 | biostudies-literature
Project description:BackgroundAbnormal macrophage function caused by dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) is a critical contributor to chronic airway infections and inflammation in people with cystic fibrosis (PWCF). Elexacaftor/tezacaftor/ivacaftor (ETI) is a new CFTR modulator therapy for PWCF. Host-pathogen and clinical responses to CFTR modulators are poorly described. We sought to determine how ETI impacts macrophage CFTR function, resulting effector functions and relationships to clinical outcome changes.MethodsClinical information and/or biospecimens were obtained at ETI initiation and 3, 6, 9 and 12 months post-ETI in 56 PWCF and compared with non-CF controls. Peripheral blood monocyte-derived macrophages (MDMs) were isolated and functional assays performed.ResultsETI treatment was associated with increased CF MDM CFTR expression, function and localisation to the plasma membrane. CF MDM phagocytosis, intracellular killing of CF pathogens and efferocytosis of apoptotic neutrophils were partially restored by ETI, but inflammatory cytokine production remained unchanged. Clinical outcomes including increased forced expiratory volume in 1 s (+10%) and body mass index (+1.0 kg·m-2) showed fluctuations over time and were highly individualised. Significant correlations between post-ETI MDM CFTR function and sweat chloride levels were observed. However, MDM CFTR function correlated with clinical outcomes better than sweat chloride.ConclusionETI is associated with unique changes in innate immune function and clinical outcomes.
| S-EPMC10066828 | biostudies-literature
Project description:ImportanceCystic fibrosis (CF) is a multiorgan genetic disease with progressive upper and lower airway involvement. The effects of CF transmembrane conductance regulator (CFTR) modifier therapies on CF-related upper airway disease, specifically chronic rhinosinusitis (CRS), are not characterized.ObjectiveTo determine the outcome of elexacaftor-tezacaftor-ivacaftor (ETI) on CRS as measured by changes in sinus computed tomography (CT) metrics and on clinical parameters in individuals with CF.Design, setting, and participantsThis prospective longitudinal cohort study was conducted at the CF center of a tertiary care hospital between October 1, 2019, and July 31, 2021. A total of 64 participants with CF were included in the analysis.InterventionSinus CT was obtained within 1 month of initiation of ETI therapy (baseline), and within 1 month of 1 year of ETI therapy. Images were independently analyzed by pulmonology, radiology, and otolaryngology physicians, using the Lund-Mackay and Sheikh-Lind scoring systems. Percent predicted forced expiratory volume in 1 second (ppFEV1), body mass index (BMI), and microbiologic data collected at initiation of ETI therapy and 3-month intervals for 1 year were also measured.Main outcomes and measuresThe study hypothesis was that ETI therapy will improve CRS as measured by changes in sinus CT at initiation and 1 year after ETI therapy and clinical parameters in individuals with CF.ResultsAmong the 64 participants (39 [60.9%] female; median age, 18.5 [IQR, 16.0-28.5] years; 64 [100%] White), improvement in CRS was noted by improvements in sinus CT scans using both sinus CT scoring systems after 1 year of ETI therapy. The reduction in the median total score using the Lund-Mackay sinus CT scoring system (from 5.8 [IQR, 5.0-7.0] to 3.3 [IQR, 2.6-4.2]) and the Sheikh-Lind scoring system (from 3.8 [IQR, 3.0-5.0] to 2.2 [IQR, 2.0-2.5]) was noted. Increases in ppFEV1 and BMI were also observed by 3 months of ETI therapy with persistent improvement through 1 year of treatment. Similarly, after 1 year of ETI therapy, participants with CF had reductions in positivity for Pseudomonas aeruginosa and Staphylococcus aureus in oropharyngeal cultures.Conclusion and relevanceThis cohort study found that use of ETI therapy was associated with improved CRS outcomes in participants with CF as quantified by improved sinus CT scans measured by 2 radiographic scoring systems and was also associated with improved clinical outcomes. Despite improvement in CT scan scores, most people with CF continue to have scores that indicate severe sinus disease.
| S-EPMC10485743 | biostudies-literature
Project description:BackgroundCystic fibrosis (CF) lung transplant (LT) recipients may warrant treatment with elexacaftor/tezacaftor/ivacaftor (ETI) to improve extrapulmonary manifestations of CF. Our objectives were to identify reasons for prescribing ETI after LT and evaluate changes in body mass index (BMI), hemoglobin A1c, hemoglobin, and liver enzymes.MethodsThis was an electronic health record-based cohort study, October 2019-September 2020, at 14 CF LT Consortium sites in North America. The study included CF LT recipients prescribed ETI after transplant. Differences in BMI, A1c, and hemoglobin were assessed with paired t-tests.ResultsThere were 94 patients prescribed ETI; indications included sinus disease (68%), GI symptoms (39%), or low BMI (19%). Prescriptions were written by CF physicians (34%), LT physicians (27%), or physicians who practice both CF and LT (39%). Forty patients (42%) stopped ETI at a median of 56 days [IQR 26, 139] after start/prescription date. ETI was not associated with a significant change in BMI (0.2 kg/m2, 95% CI [-0.1, 0.6], p = 0.150), but was associated with decreased A1c (0.4%, 95% CI 0.2, 0.7, p = 0.003), and increased hemoglobin for patients with anemia (0.6 g/dL, 95% CI 0.2, 1.0, p = 0.007). Three people (3%) stopped ETI due to elevated transaminases.ConclusionsETI is rarely prescribed for non-pulmonary indications after LT for CF. Further study is needed to determine the risks and benefits of ETI in the CF lung transplant population given the potential for drug interactions, side effects leading to discontinuation of ETI, and the possible mechanisms for ETI to positively impact long-term post-transplant outcomes.
| S-EPMC9509406 | biostudies-literature
Project description:BackgroundCFTR modulator therapies have positive clinical outcomes, yet chronic inflammation and bacterial infections persist in people with CF (pwCF). How elexacaftor-tezacaftor-ivacaftor (ETI) fails to improve innate immune signaling responsible for bacterial clearance and inflammation resolution remains unknown.MethodsWe used an unbiased proteomics approach to measure the effect of ETI on inflammatory proteins. Plasma from 20 pediatric pwCF and 20 non-CF (NCF) was collected during routine examination and 3 months after ETI initiation. Protein screening was performed with an inflammation panel (Target 96, Olink®). Bioinformatics analysis was used to determine changes in protein expression.ResultsThere were significantly fewer pulmonary exacerbations after ETI initiation, along with sustained improvement in lung function and reduced bacterial colonization. Unpaired analysis of CF pre-ETI and NCF resulted in 34 significantly different proteins. Of these, CCL20, MMP-10, EN-RAGE, and AXIN1 had a log2 fold change of 1.2 or more. There was a modest shift in overall CF protein profiles post-ETI toward the NCF cluster. Unpaired analysis of protein differential expression between NCF and CF post-ETI identified a total of 24 proteins significantly impacted by ETI therapy (p-value ≤ 0.05), with only CCL20 having a log2 fold change higher than 1.2. Paired analysis (CF pre- and CF post-ETI) of differential protein expression demonstrated significant expression changes of MMP-10, EN-RAGE, and IL-17A. Pathway analysis identified significantly impacted pathways such as the NF-κB pathway.ConclusionThis study showed that ETI in a pediatric cohort had a modest effect on several inflammatory proteins with potential as biomarkers. Pathways significantly impacted by ETI can be further studied for future therapies to combat persistent inflammation and dysregulated immunity.
| S-EPMC11811078 | biostudies-literature
Project description:BackgroundIncreased rates of respiratory adverse events have been observed in people ≥12 years of age with cystic fibrosis homozygous for the Phe508del-CFTR mutation treated with lumacaftor/ivacaftor, particularly in those with percent predicted forced expiratory volume in 1 s (ppFEV1) of <40%. We evaluated the safety, tolerability, and efficacy of tezacaftor/ivacaftor in people with cystic fibrosis homozygous for Phe508del-CFTR who discontinued lumacaftor/ivacaftor due to treatment-related respiratory signs or symptoms.MethodsParticipants ≥12 years of age with cystic fibrosis homozygous for Phe508del-CFTR with ppFEV1 of ≥25% and ≤90% were randomized 1:1 and treated with tezacaftor/ivacaftor or placebo for 56 days.ResultsOf 97 participants, 94 (96.9%) completed the study. The primary endpoint was incidence of predefined respiratory adverse events of special interest (chest discomfort, dyspnea, respiration abnormal, asthma, bronchial hyperreactivity, bronchospasm, and wheezing): tezacaftor/ivacaftor, 14.0%; placebo, 21.3%. The adverse events were mild or moderate in severity. None were serious or led to treatment interruption or discontinuation. Overall, the discontinuation rate was similar between groups. The mean (SD) ppFEV1 at baseline was 44.6% (16.1%) with tezacaftor/ivacaftor and 48.0% (18.1%) with placebo. The posterior mean difference in absolute change in ppFEV1 from baseline to the average value of days 28 and 56 was 2.7 percentage points with tezacaftor/ivacaftor vs placebo.ConclusionsTezacaftor/ivacaftor was generally safe, well tolerated, and efficacious in people ≥12 years of age with cystic fibrosis homozygous for Phe508del-CFTR with ppFEV1 of ≥25% and ≤90% who previously discontinued lumacaftor/ivacaftor due to treatment-related respiratory signs or symptoms.
| S-EPMC9187869 | biostudies-literature
Project description:The introduction of mutation-specific combination therapy with the cystic fibrosis transmembrane conductance regulator (CFTR) modulators elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has substantially improved lung function and quality of life of people with cystic fibrosis (CF). Collecting deep cough swabs and induced sputum, this postapproval study examined the effect of 14- and 50-week treatment with ELX/TEZ/IVA on the airway microbial metagenome of pancreatic- insufficient CF patients aged 12 years and older. Compared to pretreatment, the total bacterial load decreased, the individual species were more evenly distributed in the community, and the individual microbial metagenomes became more similar in their composition. However, the microbial network remained vulnerable to fragmentation. The initial shift of the CF metagenome was attributable to the ELX/TEZ/IVA-mediated gain of CFTR activity followed by a diversification driven by a group of commensals at the 1-year time point that are typical for healthy airways. IMPORTANCE Shotgun metagenome sequencing of respiratory secretions with spike-in controls for normalization demonstrated that 1 year of high-efficient CFTR modulation with elexacaftor/tezacaftor/ivacaftor extensively reduced the bacterial load. Longer observation periods will be necessary to resolve whether the partial reversion of the basic defect that is achieved with ELX/TEZ/IVA is sufficient in the long run to render the CF lungs robust against the recolonization with common opportunistic pathogens.
| S-EPMC9602284 | biostudies-literature
Project description:BackgroundElexacaftor/tezacaftor/ivacaftor (ETI) improves pulmonary disease in people with cystic fibrosis (PwCF), but its effect on gastrointestinal symptoms, which also affect quality of life, is not clear.MethodsPROMISE is a 56-center prospective, observational study of ETI in PwCF >12 years and at least one F508del allele. Gastrointestinal symptoms, evaluated by validated questionnaires: Patient Assessment of Upper Gastrointestinal Disorders-Symptom (PAGI-SYM), Patient Assessment of Constipation-Symptom (PAC-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL)), fecal calprotectin, steatocrit and elastase-1 were measured before and 6 months after ETI initiation. Mean difference and 95% confidence intervals were obtained from linear regression with adjustment for age and sex.Results438 participants fully completed at least 1 questionnaire. Mean (SD) for baseline PAGI-SYM, PAC-SYM, and PAC-QOL total scores were 0.56 (0.59), 0.47 (0.45), and 0.69 (0.53) out of maximum 5, 4, and 5, respectively (higher score indicates greater severity). Corresponding age- and sex-adjusted 6 months mean changes (95% CI) in total scores were -0.15 (-0.21, -0.09) for PAGI-SYM, -0.14 (-0.19, -0.09) for PAC-SYM, and -0.15 (-0.21, -0.10) for PAC-QOL. While statistically significant, changes were small and unlikely to be of clinical importance. Fecal calprotectin showed a change (95% CI) from baseline of -66.2 µg/g (-86.1, -46.2) at 6 months, while fecal elastase and steatocrit did not meaningfully change.ConclusionsAfter 6 months of ETI, fecal markers of inflammation decreased. Gastrointestinal symptoms improved, but the effect size was small. Pancreatic insufficiency did not improve.
| S-EPMC10144072 | biostudies-literature