Breast development in a 7 year old girl with CF treated with ivacaftor: An indication for personalized dosing?

Substantial progress has been made in the treatment of Cystic fibrosis due to introduction of CFTR modulators. However, little is known about the long term side effects of treatment with these drugs. We here present a 7 year old girl with CF who presented with breast development as a rare dose dependent side effect of treatment with ivacaftor and we report data on the correlation between drug plasma concentration and clinical effect, bodyweight, and BSA in 16 patients. Higher plasma concentrations did not correlate with clinical effect, as change in FEV1 and sweat chloride concentration. Patients with low bodyweight or BSA tended to have higher plasma concentrations. This might indicate that the current recommended dose of ivacaftor is at the top of the dose-response curve and that some patients can be treated with lower doses of ivacaftor with similar clinical effect

Clinical effects of the three CFTR potentiator treatments curcumin, genistein and ivacaftor in patients with the CFTR-S1251N gating mutation

Contains fulltext : 229853.pdf (Publisher’s version ) (Closed access)BACKGROUND: The natural food supplements curcumin and genistein, and the drug ivacaftor were found effective as CFTR potentiators in the organoids of individuals carrying a S1251N gating mutation, possibly in a synergistic fashion. Based on these in vitro findings, we evaluated the clinical efficacy of a treatment with curcumin, genistein and ivacaftor, in different combinations. METHODS: In three multi-center trials people with CF carrying the S1251N mutation were treated for 8 weeks with curcumin+genistein, ivacaftor and ivacaftor+genistein. We evaluated change in lung function, sweat chloride concentration, CFQ-r, BMI and fecal elastase to determine the clinical effect. We evaluated the pharmacokinetic properties of the compounds by evaluating the concentration in plasma collected after treatment and the effect of the same plasma on the intestinal organoids. RESULTS: A clear clinical effect of treatment with ivacaftor was observed, evidenced by a significant improvement in clinical parameters. In contrast we observed no clear clinical effect of curcumin and/or genistein, except for a small but significant reduction in sweat chloride and airway resistance. Plasma concentrations of the food supplements were low, as was the response of the organoids to this plasma. CONCLUSIONS: We observed a clear clinical effect of treatment with ivacaftor, which is in line with the high responsiveness of the intestinal organoids to this drug. No clear clinical effect was observed of the treatment with curcumin and/or genistein, the low plasma concentration of these compounds emphasizes that pharmacokinetic properties of a compound have to be considered when in vitro experiments are performed

Lumacaftor/ivacaftor in people with cystic fibrosis with an A455E-CFTR mutation

BACKGROUND: Previous in vitro organoid data showed A455E-CFTR, a rare CFTR mutation with 4.1% prevalence in the Netherlands, responds to lumacaftor/ivacaftor (LUM/IVA). We explored LUM/IVA's clinical efficacy in people with CF and ≥1 A455E-CFTR mutation. METHODS: Participants aged ≥12 years were randomized to 1 of 2 treatment sequences (LUM/IVA→placebo or placebo→LUM/IVA) with an 8-week washout period between. Primary endpoint was absolute change in ppFEV1 from study baseline through 8 weeks. Additional endpoints were change in sweat chloride concentration (SwCl) and CFQ-R respiratory domain score. Correlations between organoid-based measurements and clinical endpoints were investigated. RESULTS: Twenty participants were randomized at 2 sites in the Netherlands. Mean absolute change in ppFEV1 from study baseline through Week 8 showed a treatment difference of 0.1 percentage points (95% CI, -2.5 to 2.7; P = 0.928) between LUM/IVA (within-group mean change, 2.7) and placebo (within-group mean change, 2.6). The mean absolute change in SwCl concentration from study baseline through Week 8 showed a treatment difference of -7.8 mmol/L between LUM/IVA and placebo (P = 0.004), while the absolute change in CFQ-R respiratory domain score showed a treatment difference of 3.5 between LUM/IVA and placebo (P = 0.469). The in vitro organoid-based assay demonstrated a concentration-dependent swelling increase with LUM/IVA. Exploratory correlation analyses between organoid swelling and ppFEV1 and SwCl outcomes showed correlation coefficients of 0.49 and -0.11, respectively. CONCLUSIONS: In this exploratory study, LUM/IVA elicited an in vitro response in organoid swelling and in vivo response in SwCl in participants with CF and ≥1 A455E-CFTR mutation. The primary endpoint (ppFEV1) did not show a statistically significant difference between LUM/IVA and placebo; correlations between in vitro and in vivo responses were not established (NCT03061331)

Forskolin-induced Organoid Swelling is Associated with Long-term CF Disease Progression

RATIONALE: Cystic fibrosis (CF) is a monogenic life-shortening disease associated with highly variable individual disease progression which is difficult to predict. Here we assessed the association of forskolin-induced swelling (FIS) of patient-derived organoids (PDO) with long-term CF disease progression in multiple organs and compared FIS with the golden standard biomarker sweat chloride concentration (SCC). METHODS: We retrieved 9-year longitudinal clinical data from the Dutch CF Registry of 173 people with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Individual CFTR function was defined by FIS, measured as the relative size increase of intestinal organoids after stimulation with 0.8 µM forskolin, quantified as area under the curve (AUC). We used linear mixed effect models and multivariable logistic regression to estimate the association of FIS with long-term FEV1pp decline and development of pancreatic insufficiency, CF-related liver disease and diabetes. Within these models, FIS was compared with SCC. RESULTS: FIS was strongly associated with longitudinal changes of lung function, with an estimated difference in annual FEV1pp decline of 0.32% (95%CI: 0.11%-0.54%; p=0.004) per 1000-points change in AUC. Moreover, increasing FIS levels were associated with lower odds of developing pancreatic insufficiency (adjusted OR: 0.18, 95%CI: 0.07-0.46, p<0.001), CF-related liver disease (adjusted OR: 0.18, 95%CI: 0.06-0.54, p=0.002) and diabetes (adjusted OR: 0.34, 95%CI: 0.12-0.97, p=0.044). These associations were absent for SCC. CONCLUSION: This study exemplifies the prognostic value of a PDO-based biomarker within a clinical setting, which is especially important for people carrying rare CFTR mutations with unclear clinical consequences

Personalizing CFTR modulator therapies

over 2000 genetic mutations that can cause CF, resulting in many phenotypes. Recently new drugs were developed that treat the disease at the origin of the problem; they enhance the function of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein which is not functioning properly in CF. These potentially life saving drugs are currently only available for part of the CF population and especially patients with a rare mutation often don’t qualify for a treatment. By culturing stem cells of a patient in the lab, we can generate organoid which can be seen as a sort of mini-organs. This culture technique generates many options for research and individualised drug testing without the need to test a treatment in a patient. Research in this thesis shows how intestinal organoids can be used to treat patients with CF. It shows for example how organoids can be used to identify effective treatments for (groups of) patients. Because of this research a number of CF patients with a rare CFTR mutation was already successfully selected for a life changing treatment. This thesis also provides the basis for a current European study in which treatments are selected for about 2000 European CF patients with a rare CFTR mutation. It is expected that in the near future the organoid model can not only be used for research in patients with CF but also for patients with other diseases

Personalizing CFTR modulator therapies

over 2000 genetic mutations that can cause CF, resulting in many phenotypes. Recently new drugs were developed that treat the disease at the origin of the problem; they enhance the function of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein which is not functioning properly in CF. These potentially life saving drugs are currently only available for part of the CF population and especially patients with a rare mutation often don’t qualify for a treatment. By culturing stem cells of a patient in the lab, we can generate organoid which can be seen as a sort of mini-organs. This culture technique generates many options for research and individualised drug testing without the need to test a treatment in a patient. Research in this thesis shows how intestinal organoids can be used to treat patients with CF. It shows for example how organoids can be used to identify effective treatments for (groups of) patients. Because of this research a number of CF patients with a rare CFTR mutation was already successfully selected for a life changing treatment. This thesis also provides the basis for a current European study in which treatments are selected for about 2000 European CF patients with a rare CFTR mutation. It is expected that in the near future the organoid model can not only be used for research in patients with CF but also for patients with other diseases

Tuchtrechtelijke uitspraken inzake kindermishandeling : Lessen voor de kinderarts

Objective: To give an overview of disciplinary cases regarding action taken by paediatricians and paediatric residents in cases of (suspected) child abuse and to discuss the considerations of the disciplinary board in these cases. Design: Retrospective, descriptive study. Method: We considered all disciplinary cases instigated from 2001 to 2013 against paediatricians or paediatric residents and selected complaints regarding action taken in cases of (suspected) child abuse. We divided these complaints into six categories and studied the considerations of the disciplinary board in these cases. Results: From 33 disciplinary cases instigated from 2001 to 2013, we selected 76 complaints regarding action taken by paediatricians or paediatric residents in cases of (suspected) child abuse. The majority of these complaints concerned the reporting or requesting of information in the context of (suspected) child abuse. All of the complaints in the category 'unwarranted reporting of child abuse' were declared unfounded by the disciplinary judge. Conclusion: The disciplinary board declared all complaints unfounded in cases where the paediatrician or paediatric resident had followed the Dutch national protocol regarding reporting of child abuse and domestic violence. The disciplinary board examines whether action was taken in accordance with reasonable standards of professional competence and considers that paediatricians have an important role in identifying child abuse

The impact of ivacaftor on sinonasal pathology in S1251N-mediated cystic fibrosis patients.

ImportanceSinonasal symptoms in patients suffering from cystic fibrosis can negatively influence the quality of life and sinuses can be a niche for pathogens causing infection and inflammation leading to a decrease of lung function. Ivacaftor, a potentiator of the Cystic Fibrosis Transmembrane Conductance Regulator protein, has shown improvement in pulmonary function in cystic fibrosis patients with different forms of class III gating mutations. However, the effects of ivacaftor on sinonasal pathology have hardly been studied.ObjectiveTo determine the impact of ivacaftor therapy on sinonasal pathology in patients with cystic fibrosis with an S1251N mutation.DesignProspective observational mono-center cohort study, between June 2015 and December 2016.SettingA tertiary referral center in Utrecht, The Netherlands.ParticipantsEight patients with cystic fibrosis with an S1251N mutation, treated with the potentiator ivacaftor were investigated.ExposuresIvacaftor (Kalydeco, VX-770) therapy. Computed tomography imaging of paranasal sinuses. Nasal nitric oxide concentration measurements and nasal endoscopy.Main outcomes and measuresPrimary outcome is opacification of paranasal sinuses examined with computed tomography scan analysis and scaled by the modified Lund-Mackay score before and one year after treatment. Secondary outcomes are nasal nitric oxide concentration levels, sinonasal symptoms and nasal endoscopic findings before and approximately two months and in some cases one year after treatment.ResultsComputed tomography scan analysis showed a significant decrease in opacification of the majority of paranasal sinuses comparing the opacification score per paranasal sinus before and after one year of treatment with ivacaftor. Median nasal nitric oxide levels significantly improved from 220.00 (IQR:136.00-341.18) to 462.84 (IQR:233.17-636.25) (p = 0.017) parts per billion. Likewise, the majority of sinonasal symptoms and nasal endoscopic pathology decreased or resolved at two months after the use of ivacaftor.Conclusion and relevanceIvacaftor appears to improve sinonasal outcome parameters and thereby sinonasal health in patients with cystic fibrosis with an S1251N mutation

IVACAFTOR restores FGF19 regulated bile acid homeostasis in cystic fibrosis patients with an S1251N or a G551D gating mutation

Objective: Disruption of the enterohepatic circulation of bile acids (BAs) is part of the gastrointestinal phenotype of cystic fibrosis (CF). Ivacaftor (VX-770), a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, improves pulmonary function in CF patients with class III gating mutations. We studied the effect of ivacaftor on the enterohepatic circulation by assessing markers of BA homeostasis and their changes in CF patients. Methods: In CF patients with an S1251N mutation (N = 16; age 9–35 years S125N study/NTR4873) or a G551D mutation (N = 101; age 10–24 years; GOAL study/ NCT01521338) we analyzed plasma fibroblast growth factor 19 (FGF19) and 7α-hydroxy-4-cholesten-3-one (C4) levels, surrogate markers for intestinal BA absorption and hepatic synthesis, respectively, before and after treatment with ivacaftor. Results: At baseline, median FGF19 was lower (52% and 53%, P <.001) and median C4 higher (350% and 364%, P <.001), respectively, for the S1251 N and G551D mutation patient groups compared to healthy controls. Treatment with ivacaftor significantly increased FGF19 and reduced C4 levels towards normalization in both cohorts but this did not correlate with CFTR function in other organs, as measured by sweat chloride levels or pulmonary function. Conclusions: We demonstrate that patients with CFTR gating mutations display interruption of the enterohepatic circulation of BAs reflected by lower FGF19 and elevated C4 levels. Treatment with ivacaftor partially restored this disruption of BA homeostasis. The improvement did not correlate with established outcome measures of CF, suggesting involvement of modulating factors of CFTR correction in different organs

Rectal Organoids Enable Personalized Treatment of Cystic Fibrosis

Contains fulltext : 201349.pdf (publisher's version ) (Open Access