Elexacaftor/tezacaftor/ivacaftor in liver or kidney transplanted people with cystic fibrosis using tacrolimus, a drug-drug interaction study.

BACKGROUND: The use of elexacaftor/tezacaftor/ivacaftor (ETI) in people with cystic fibrosis (pwCF) after solid organ transplantation is controversial because of potential drug-drug interactions (DDI) with tacrolimus. We aimed to improve insight into the safety and clinical benefits of co-administration of ETI and tacrolimus in liver or kidney transplanted adult pwCF. METHODS: In 5 pwCF, tacrolimus concentrations were monitored during 2 weeks before and 4 weeks after starting ETI treatment. Trough levels, area under the curve (AUC) and clinical effect of ETI were investigated. During the study (6 weeks in total) adverse events were monitored. RESULTS: The DDI between tacrolimus and ETI resulted in an increased exposure of tacrolimus in all subjects, the dose adjusted AUC0-24h was 1.79 (median) times higher at the end of the study. Five dose adjustments were performed in 4 subjects in order to attain tacrolimus target range. No adverse events were reported and all subjects showed clinical improvement during ETI treatment. CONCLUSION: The clinical value of ETI treatment in kidney and liver transplanted pwCF is clear. The use of ETI may increase tacrolimus levels moderately. Therefore, we recommend close monitoring of tacrolimus trough levels in patients who start ETI.

The prevalence of vascular and metabolic complications after lung transplant in people with cystic fibrosis in a Dutch cohort.

BACKGROUND: With improvements in care for people with Cystic Fibrosis (pwCF), total survival after Lung Transplantation (LTx) will be longer. Therefore, this population's up-to-date analysis of late-onset post-transplant metabolic and vascular complications will be more relevant in current clinical practice. METHODS: We studied 100 pwCF who underwent an LTx between 2001 and 2020 at the University Medical Centre Utrecht, the Netherlands. The median age at transplant was 31 years and 55 percent was male. We assessed survival, the prevalence of metabolic complications (diabetes, renal damage, dyslipidemia, and metabolic syndrome), and vascular complications (hypertension, heart rhythm disease, micro-, and macrovascular disease). In addition, differences in risks for developing complications based on sex and overall survival were analyzed. RESULTS: The prevalence of macrovascular disease raised to 15.9 percent 15 years post-LTx. The prevalence of diabetes increased from 63 percent at LTx to over 90 percent 15 years post-LTx and the prevalence of dyslipidemia increased from 21 percent to over 80 percent. Survival 1-, 2-, 5-, and 10 years post-transplant were 84, 80, 76, and 58 percent respectively. No significant differences were found based on sex. CONCLUSION: This study shows that the prevalence of cardiovascular risk factors increases after LTx for CF, potentially leading to major complications. These data emphasize the necessity of regular check-ups for metabolic and vascular complications after LTx with specific attention to renal damage. Early recognition of these complications is crucial and will lead to earlier intervention, which could lead to improved prognosis after lung transplantation.

Development and validation of a novel personalized electronic patient-reported outcome measure to assess quality of life (Q-LIFE): a prospective observational study in people with Cystic Fibrosis.

Background: Generic and disease-specific patient-reported outcome measures (PROMs) may lack relevance and sensitivity on a patient-level in chronic diseases with differential disease expression and high individual variability, such as Cystic Fibrosis (CF). This study aimed to develop and validate a novel personalized electronic PROM (ePROM) that captures relevant aspects of quality of life in individuals with CF. Methods: The Q-Life app was developed as a short personalized ePROM to assess individual quality of life. Psychometric properties were assessed in a single-center cross-sectional study between September 2019 and September 2021 and in a prospective cohort study between September 2021 and September 2022. Findings: Combined studies included 223 participants (median age: 24 years, IQR: 19.0-32.5 years, range: 12.0-58.0 years). Internal consistency (Cronbach's alpha: 0.83-0.90) and test-retest reliability (intraclass correlation coefficient: 0.90; 95% CI: 0.65-0.92; p < 0.001) of quality of life (Q-Life) scores were strong. Q-Life scores were associated with overall Cystic Fibrosis Questionnaire-Revised (CFQ-R) scores (ρ = 0.71; p < 0.001), CFQ-R respiratory domain scores (ρ = 0.57; p < 0.001) and forced expiratory volume in 1s (ρ = 0.41; p < 0.001). Furthermore, Q-Life scores improved from 65.0 (IQR: 45.0-63.3) at baseline to 84.2 (IQR: 75.0-95.0) and 87.5 (IQR: 75.0-100.0) after 3 and 6 months of elexacaftor/tezacaftor/ivacaftor treatment (change: 20.8; 95% CI: 17.5-25.0; p < 0.001), comparable to CFQ-R respiratory domain scores (change: 22.2, 95% CI: 19.4-25.0, p < 0.001). Interpretation: The Q-Life app is a reliable, valid and sensitive personalized ePROM to measure all aspects of quality of life that really matter to individuals with Cystic Fibrosis. This patient-centered approach could provide important advantages over generic and disease-specific PROMs in the era of personalized medicine and value-based healthcare. Funding: Dutch Cystic Fibrosis Foundation, Health-Holland.

Radiological and long-term clinical response to elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis with advanced lung disease.

INTRODUCTION: A triple combination of CFTR modulators ELE/TEZ/IVA (elexacaftor/tezacaftor/ivacaftor, Trikafta™) has been evaluated in clinical trials for people with cystic fibrosis (pwCF) and was approved to the European and US market. During registration and settling reimbursement in Europe, it could be requested on a compassionate use basis, for patients with advanced lung disease (ppFEV1 < 40). AIM: The aim of this study is to evaluate 2 years of experience with the clinical and radiological response of ELE/TEZ/IVA in pwCF in a compassionate use setting. METHODS: pwCF who started ELE/TEZ/IVA in a compassionate use setting were prospectively followed with assessment of spirometry, BMI, chest CT, CFQ-R and sweat chloride concentration (SCC) before start and after 3 months. Furthermore, spirometry, sputum cultures, and BMI were repeated after 1, 6, 12, 18, and 24 months. RESULTS: Eighteen patients were eligible for this evaluation, nine with F508del/F508del genotype (eight of whom were using dual CFTR modulators) and nine with F508del/minimal function mutation. After 3 months, mean change in SCC was -44.9 (p ≤ 0.001), together with significant improvement in CT (change in Brody score: -28.27 p ≤ 0.001) and CFQ-R results (change in respiratory domain: +18.8, p = 0.002). After 24 months, ppFEV1 change was +8.89 (p = 0.002), BMI had improved by +1.53 kg/m2 (p ≤ 0.001) and exacerbation rate declined from 5.94 in 24 months before start to 1.17 (p ≤ 0.001) in the 24 months after. CONCLUSION: pwCF with advanced lung disease experience relevant clinical benefit after 2 years of treatment with ELE/TEZ/IVA in a compassionate use setting. Structural lung damage, quality of life, exacerbation rate, and BMI improved significantly with treatment. Gain in ppFEV1 is lower compared to the phase III trials that included younger patients with moderately affected lung function.

Robot-assisted and fluorescence-guided remnant-cholecystectomy: a prospective dual-center cohort study.

BACKGROUND: Abdominal symptoms after cholecystectomy may be caused by gallstones in a remnant gallbladder or a long cystic duct stump. Resection of a remnant gallbladder or cystic duct stump is associated with an increased risk of conversion and bile duct or vascular injuries. We prospectively investigated the additional value of robotic assistance and fluorescent bile duct illumination in redo biliary surgery. METHODS: In this prospective two-centre observational cohort study, 28 patients were included with an indication for redo biliary surgery because of remnant stones in a remnant gallbladder or long cystic duct stump. Surgery was performed with the da Vinci X® and Xi® robotic system. The biliary tract was visualised in the fluorescence Firefly® mode shortly after intravenous injection of indocyanine green. RESULTS: There were no conversions or perioperative complications, especially no vascular or bile duct injuries. Fluorescence-based illumination of the extrahepatic bile ducts was successful in all cases. Symptoms were resolved in 27 of 28 patients. Ten patients were treated in day care and 13 patients were discharged the day after surgery. CONCLUSION: Robot-assisted fluorescence-guided surgery for remnant gallbladder or cystic duct stump resection is safe, effective and can be done in day-care setting.

Development and outcomes of a patient driven cystic fibrosis quality of care improvement project.

The Dutch CF Foundation (NCFS) developed a quality improvement program, to assess and improve quality of care in all CF centers in The Netherlands. Criteria to assess quality of care from the patient perspective were defined, and quality of care was assessed by patients via online surveys and site visits. Recommendations were addressed to all centers to improve quality of care. Most recommendations were related to communicational issues. All centers were given the quality mark of the patient organisation, although two of them needed extra time to meet the lower limit of the core set of criteria. After two years, over 75 % of the recommendations given to the centers were fully or partly implemented, showing a high efficacy of the program.

The influence of exocrine pancreatic function on the exposure and pharmacokinetics of ivacaftor in people with cystic fibrosis.

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies target the underlying cause of cystic fibrosis (CF), and show robust treatment effects at group level. The individual effect however, is variable which might be (partially) related to differences in drug exposure. The profound influence of fat containing food compared to fasting on drug exposure gives need to investigate if the exocrine pancreatic function changes the degree and rate of absorption of ivacaftor and thereby may contribute to differences in drug exposure. METHODS: Pharmacokinetic parameters of ivacaftor were measured in 10 pancreatic sufficient (PS) and 10 pancreatic insufficient (PI) patients with CF on current treatment with tezacaftor/ivacaftor and compared between both groups. In PI patients pharmacokinetic parameters were investigated with and without the use pancreatic enzymes and compared in each individual. RESULTS: We demonstrated that the pharmacokinetic parameters of ivacaftor did not differ significantly between PS and PI people with CF (pwCF). Pancreatic enzymes did not significantly change the absorption or exposure to ivacaftor in PI pwCF using tezacaftor/ivacaftor. CONCLUSION: The exocrine pancreatic function of pwCF does not significantly influence the absorption and exposure of ivacaftor. The use of pancreatic enzymes in PI pwCF does not change the absorption and exposure of ivacaftor. Therefore, the dosing advice as mentioned in the SmPC for ivacaftor can be maintained independent of the exocrine pancreatic function.

The prevalence of vascular and metabolic complications after lung transplant in people with cystic fibrosis in a Dutch cohort

Abstract Background With improvements in care for people with Cystic Fibrosis (pwCF), total survival after Lung Transplantation (LTx) will be longer. Therefore, this population's up-to-date analysis of late-onset post-transplant metabolic and vascular complications will be more relevant in current clinical practice. Methods We studied 100 pwCF who underwent an LTx between 2001 and 2020 at the University Medical Centre Utrecht, the Netherlands. The median age at transplant was 31 years and 55 percent was male. We assessed survival, the prevalence of metabolic complications (diabetes, renal damage, dyslipidemia, and metabolic syndrome), and vascular complications (hypertension, heart rhythm disease, micro-, and macrovascular disease). In addition, differences in risks for developing complications based on sex and overall survival were analyzed. Results The prevalence of macrovascular disease raised to 15.9 percent 15 years post-LTx. The prevalence of diabetes increased from 63 percent at LTx to over 90 percent 15 years post-LTx and the prevalence of dyslipidemia increased from 21 percent to over 80 percent. Survival 1-, 2-, 5-, and 10 years post-transplant were 84, 80, 76, and 58 percent respectively. No significant differences were found based on sex. Conclusion This study shows that the prevalence of cardiovascular risk factors increases after LTx for CF, potentially leading to major complications. These data emphasize the necessity of regular check-ups for metabolic and vascular complications after LTx with specific attention to renal damage. Early recognition of these complications is crucial and will lead to earlier intervention, which could lead to improved prognosis after lung transplantation.

Effects of long-term tobramycin inhalation solution (TIS) once daily on exacerbation rate in patients with non-cystic fibrosis bronchiectasis.

BACKGROUND: Use of long-term tobramycin inhalation solution (TIS) has been shown beneficial in cystic fibrosis (CF) and earlier findings also suggest a benefit in non-CF bronchiectasis. We investigated the efficacy and safety of maintenance TIS once daily (OD) in frequent exacerbating bronchiectasis patients chronically infected by different pathogens sensitive for tobramycin. OBJECTIVE: The primary outcome was the frequency of exacerbations during the 12-month study period. Secondary outcomes were time to first exacerbation, change in lung function and quality of life (QoL), bacterial analysis and safety. MATERIALS/PATIENTS: IN THIS MULTICENTER RCT PATIENTS AGED ≥ 18-YEAR-OLD WERE INCLUDED WITH CONFIRMED BRONCHIECTASIS AND ≥ 2 EXACERBATIONS IN THE PRECEDING YEAR. PATIENTS WERE ASSIGNED (1:1) TO RECEIVE TIS OR PLACEBO OD FOR 1-YEAR.: RESULTS: 58 patients were included of which 52 were analyzed in the mITT analysis. TIS reduced exacerbation frequency with a RR of 0.74 (95% CI 0.49-1.14) (p = 0.15). Within the TIS population a decrease in number of exacerbations was found (2; p = 0.00), which was also seen in the placebo-treated patients (1.5; p = 0.00). In the TIS-treated patients the QoL improved (LRTI-VAS p = 0.02 Leicester Cough p = 0.02) without additional safety concerns. No differences were found for the other secondary outcomes. CONCLUSION: Long-term TIS OD is a safe treatment modality and showed a non-significant reduced exacerbation frequency of 0.74 as compared to placebo in bronchiectasis patients chronically infected by tobramycin sensitive pathogens. TIS OD may be a potential therapeutic strategy in selected patients with bronchiectasis suffering from a high burden of disease. TRAIL REGISTRATION NUMBER: The BATTLE study was registered at Clinical trials.gov number: NCT02657473 . Date: 13 august 2016.

Physiological predictors of cardiorespiratory fitness in children and adolescents with cystic fibrosis without ventilatory limitation.

OBJECTIVES: [1] To investigate the cardiorespiratory fitness (CRF) levels in children and adolescents with cystic fibrosis (CF) with no ventilatory limitation (ventilatory reserve ⩾ 15%) during exercise, and [2] to assess which physiological factors are related to CRF. METHODS: A cross-sectional study design was used in 8- to 18-year-old children and adolescents with CF. Cardiopulmonary exercise testing was used to determine peak oxygen uptake normalized to body weight as a measure of CRF. Patients were defined as having 'low CRF' when CRF was less than 82%predicted. Physiological predictors used in this study were body mass index z-score, P. Aeruginosa lung infection, impaired glucose tolerance (IGT) including CF-related diabetes, CF-related liver disease, sweat chloride concentration, and self-reported physical activity. Backward likelihood ratio (LR) logistic regression analysis was used. RESULTS: Sixty children and adolescents (51.7% boys) with a median age of 15.3 years (25th-75th percentile: 12.9-17.0 years) and a mean percentage predicted forced expiratory volume in 1 second of 88.5% (±16.9) participated. Mean percentage predicted CRF (ppVO2peak/kg) was 81.4% (±12.4, range: 51%-105%). Thirty-three patients (55.0%) were classified as having 'low CRF'. The final model that best predicted low CRF included IGT (p = 0.085; Exp(B) = 6.770) and P. Aeruginosa lung infection (p = 0.095; Exp(B) = 3.945). This model was able to explain between 26.7% and 35.6% of variance. CONCLUSIONS: CRF is reduced in over half of children and adolescents with CF with normal ventilatory reserve. Glucose intolerance and P. Aeruginosa lung infection seem to be associated to low CRF in children and adolescents with CF.

The effect of maintenance azithromycin on radiological features in patients with bronchiectasis - Analysis from the BAT randomized controlled trial.

RATIONALE: Bronchiectasis (abnormal dilatation of bronchi) is usually diagnosed by high resolution computed tomography (HRCT) and radiological severity has been found to correspond with clinical outcome. A beneficial effect of macrolides maintenance treatment in frequent exacerbating bronchiectasis patients has been established in randomized trials. This study was undertaken to prospectively evaluate the effect of long-term azithromycin (AZM) on radiological features in patients with bronchiectasis. METHODS: The BAT randomized controlled trial (2008-2010) investigated the effect of 1 year of AZM (250 mg OD) in bronchiectasis with frequent exacerbations. Chest (HR)CT-scans at baseline and after one year of study treatment were obtained and scored by two radiologists according to the Brody - and the Bhalla scoring system. RESULTS: 77 (93%) patients conducted the BAT trial were evaluated in this post-hoc analysis. A significant improvement of the radiological features based on the Brody score was found after one year of AZM therapy as compared to placebo (p = 0.024), with a not significant improvement of the Bhalla score (p=0.071). Especially the consolidation (Bhalla) and parenchymal changes (Brody) sub scores significantly improved (both p=0.030), and even a radiological deterioration was seen on the Brody bronchiectasis sub score for the placebo treated patients (mean 14.5 (11.7) vs.15.7 (11.9)). CONCLUSIONS: The beneficial effect of long-term AZM treatment on radiological features was demonstrated in this randomized controlled trial. (HR)CT's can be used as an objective measure of treatment response in bronchiectasis. CLINICAL TRIAL REGISTRATION NUMBER: NCT00415350.

Targeted exhaled breath analysis for detection of Pseudomonas aeruginosa in cystic fibrosis patients.

BACKGROUND: Pseudomonas aeruginosa (PA) is an important respiratory pathogen for cystic fibrosis (CF) patients. Routine microbiology surveillance is time-consuming, and is best performed on expectorated sputum. As alternative, volatile organic compounds (VOCs) may be indicative of PA colonisation. In this study, we aimed to identify VOCs associated with PA in literature and perform targeted exhaled breath analysis to recognize PA positive CF patients non-invasively. METHODS: This study consisted of 1) a literature review to select VOCs of interest, and 2) a cross-sectional CF study. Definitions used: A) PA positive, PA culture at visit/chronically; B) PA free, no PA culture in ≥12 months. Exhaled VOCs were identified via quadrupole MS. The primary endpoint was the area under the receiver operating characteristics curve (AUROCC) of individual VOCs as well as combined VOCs against PA culture. RESULTS: 241 VOCs were identified in literature, of which 56 were further evaluated, and 13 could be detected in exhaled breath in our cohort. Exhaled breath of 25 pediatric and 28 adult CF patients, PA positive (n=16) and free (n=28) was available. 3/13 VOCs were significantly (p<0.05) different between PA groups in children; none were in adults. Notably, a composite model based on 5 or 1 VOC(s) showed an AUROCC of 0.86 (CI 0.71-1.0) and 0.87 (CI 0.72-1.0) for adults and children, respectively. CONCLUSIONS: Targeted VOC analysis appears to discriminate children and adults with and without PA positive cultures with clinically acceptable sensitivity values.

Fluorescence-Based Quantification of Gastrointestinal Perfusion: A Step Towards an Automated Approach.

Background: Qualitative fluorescence angiography (FA) provides insights into intestinal tissue perfusion, but today it is not yet accurate in predicting anastomotic leakage. To improve peroperative detection of impaired perfusion, quantified parameters should be investigated using a standardized method. The aim of this study was to develop a (semi)automated algorithm for comprehensive and convenient analysis of FA parameters. Materials and Methods: An analysis tool was developed for the extraction of quantified FA parameters. The start- and endpoint of intensity increase (T0 and Tmax) were automatically detected in the intensity-time curves. Algorithm performance was measured against manual assignment of T0 and Tmax by 9 independent observers in 18 in vivo generated test signals, using the intraclass correlation coefficient (ICC). Characteristics of parameter T1∕2 (time to 50% of maximal intensity) were analyzed in normally perfused small intestine of 32 subjects who underwent robotic laparoscopic surgery. Since ethical approval was not required under the Dutch law, the need for informed consent was waived. Results: Automated detection of T0 and Tmax was successful in all subjects. Output of the algorithm had an excellent agreement with the median of the human observations: ICC = 0.95 (95% confidence interval: 0.86-0.96). Overall, T1∕2 had a median value of 5.1 (interquartile range = 2.4) seconds and a minimal and maximal value of 1.3 and 9.9 seconds, respectively. Conclusions: The presented method provided convenient data analysis in the search for effective FA quantification. Future research should expand the data to find adequate threshold values for peroperatively identifying insufficient perfusion and investigate the influence of physiological conditions.

Management of Individual Patient Expectations When Starting with Highly Effective CFTR Modulators.

Highly effective CFTR modulators such as elexacaftor/tezacaftor/ivacaftor (ELE/TEZ/IVA will become available for an increasing number of people with cystic fibrosis (pwCF) in the near future. Before the start of this therapy, many questions may arise concerning the expected effects. We assembled the currently available data from the literature about ELE/TEZ/IVA that focused on commonly asked questions from patients. Overall, the literature so far presents a very hopeful prospect of effects, not only on lung function, but also on nutritional status, sinonasal symptoms and quality of life. The effects in patients with pwCF with severe lung damage are also favorable. Treatment is generally well tolerated. In some cases, patient-derived cell models can help in predicting the effects for individual patients.

CFTR Modulators: Does One Dose Fit All?

For many people with cystic fibrosis (pwCF), CFTR modulators will be the cornerstone of their treatment. These modulators show robust treatment effects at group level in pwCF with specific mutations. The individual effect however, is variable. In this review we will explain reasons for reconsideration of dosing regimens of CFTR modulating therapy in order to improve treatment response and prevent side effects. Since the effect of a drug depends on pharmacodynamics and pharmacokinetics, pharmacodynamics and pharmacokinetic properties of CFTR modulators will be discussed. Pharmacokinetic-pharmacodynamic relationships will be used to gain insight in dosage response and exposure response relationships. To understand the cause of variation in drug exposure, pharmacokinetic properties that may change due to CF disease will be explained. We show that with current insight, there are conceivable situations that give reason for reconsideration of dosing regimens, however many questions need to be unravelled.

Pharmacokinetic interactions between ivacaftor and cytochrome P450 3A4 inhibitors in people with cystic fibrosis and healthy controls.

BACKGROUND: Ivacaftor is currently the only CFTR potentiator approved and is increasingly used since the development of CFTR correctors. Ivacaftor is metabolized by CYP3A4 and therefore dose reduction is required when treating patients on ivacaftor with CYP3A4 inhibiting drugs. As this advice is based on studies in healthy volunteers and not in cystic fibrosis (CF) patients, we need to investigate this in both groups to be able to extrapolate these data to CF. METHODS: A cohort of CF patients and healthy subjects were exposed to a single dose of ivacaftor in combination with a strong (ritonavir), moderate (clarithromycin) and mild (azithromycin) CYP3A4 inhibitor. Ivacaftor concentrations were measured in all blood samples in order to calculate the pharmacokinetic parameters for ivacaftor. RESULTS: We found that exposure to ivacaftor was higher in healthy volunteers than in subjects with CF. However this difference was not statistically significant. No differences were observed in the interaction potential of CYP3A4 inhibitors between both study groups. The strong CYP3A4 inhibitor ritonavir, increased exposure to ivacaftor 7 times. CONCLUSION: Our data support current recommendations for dose adjustment of ivacaftor in case of co-treatment with CYP3A4 inhibitors in people with CF. However, exposure to ivacaftor was higher in healthy subjects than in CF patients. Further study is needed to investigate the cause and implication of this difference.

Individual and Group Response of Treatment with Ivacaftor on Airway and Gut Microbiota in People with CF and a S1251N Mutation.

Ivacaftor has been shown to restore the functionality of the S1251N (also known as c.3752G>A) mutated CFTR, which may cause alterations in both airway and gut physiology and micro-environment, resulting in a change of microbiota in these organs. The aim of the present study was to analyze the effects of ivacaftor on the microbial community composition of both airway and gut in subjects with CF carrying one S1251N mutation, using a 16S rRNA gene-based sequencing approach. In 16 subjects with CF, repetitive samples from airways and gut were collected just before, and 2 months after, and, for 8 patients, also 9 and 12 months after, start of ivacaftor. 16S rRNA based sequencing identified 344 operational taxonomical units (OTUs) in a total of 139 samples (35 nasopharyngeal, 39 oropharyngeal, 29 sputum, and 36 fecal samples). Ivacaftor significantly enhanced bacterial diversity and overall microbiota composition in the gut (p < 0.01). There were no significant changes in the overall microbial composition and alpha diversity in upper and lower airways of these patients after ivacaftor treatment. Treatment with ivacaftor induces changes in gut microbiota whereas airway microbiota do not change significantly over time.

Does Circadian Rhythm Affect the Pharmacokinetics of Once-Daily Tobramycin in Adults With Cystic Fibrosis?

BACKGROUND: In the era of multiple daily dosing of systemic aminoglycosides, a circadian rhythm in the clearance of these vital antibiotics has been demonstrated in animals and healthy volunteers. Over the past decade, once-daily dosing regimens have been proved to be less nephrotoxic and were therefore adopted worldwide for most indications requiring treatment with an aminoglycoside. In this study, the effect of the time of administration on the pharmacokinetics of once-daily tobramycin in adults with cystic fibrosis (CF) experiencing a pulmonary exacerbation was investigated. METHODS: In this open randomized study, patients with CF received intravenous tobramycin at 8:00 or 22:00 hours. Pharmacokinetic and kidney function parameters were compared between the 2 groups. RESULTS: Twenty-five patients were included. The mean weight-corrected clearances of tobramycin were 1.46 versus 1.43 mL/h*kg (P = 0.50) and mean volumes of distribution were 0.25 versus 0.27 L/kg (P = 0.54) for the 8:00 and 22:00 groups, respectively. In addition, no significant differences were detected in changes in estimated clearances of creatinine or tobramycin on day 1 and day 8 in the 8:00 or 22:00 group, indicating that there was no decline in clearance over time. At day 8 of therapy, the increase in serum blood urea nitrogen in the 22:00 group was significantly higher than that in the 8:00 group (1.8 versus 0.2 mmol/L, P = 0.015). CONCLUSIONS: The time of administration (8:00 versus 22:00) did not affect tobramycin pharmacokinetics in the adult CF population studied. The increase in serum blood urea nitrogen in the 22:00 group requires further investigation.

Forskolin-induced swelling of intestinal organoids correlates with disease severity in adults with cystic fibrosis and homozygous F508del mutations.

BACKGROUND: CFTR function measurements in intestinal organoids may help to better characterise individual disease expression in F508del homozygous people. Our objective was to study correlations between CFTR function as measured with forskolin-induced swelling in rectal organoids with clinical parameters in adult patients with homozygous F508del mutations. METHODS: Multicentre observational study. Thirty-four adults underwent rectal biopsy, pulmonary function tests (FEV1 and FVC), chest X-ray and chest CT. Body-mass index (BMI) was assessed at study visit and exacerbation rate was determined during five years prior to study visit. Organoids were cultured and measured after stimulation with 5 µm forskolin for three hours to quantitate CFTR residual function. FINDINGS: FIS was positively correlated with FEV1 (r = 0.36, 95% CI 0.02-0.62, p = 0.04) and BMI (r = 0.42, 95% CI 0.09-0.66, p = 0.015). FIS was negatively correlated with PRAGMA-CF CT score for% of disease (r = -0.37, 95% CI -0.62- -0.03, p = 0.049). We found no significant correlation between FIS and chest radiography score for CF (r = -0.16, 95% CI -0.48-0.20, p = 0.44). We observed a trend between higher FIS and a lower mean number of exacerbations over the last 5 years of observation, but this was not statistically significant (Poisson regression, p = 0.089). INTERPRETATION: FIS of intestinal organoids varied between subjects with homozygous F508del and correlated with pulmonary and nutritional parameters. These findings suggest that differences at low CFTR residual function may contribute to clinical heterogeneity in F508del homozygous patients and small changes in CFTR residual function might impact long-term disease expression.