Assuntos
Agonistas dos Canais de Cloreto , Fibrose Cística , Transtornos do Sono-Vigília , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Aminofenóis/efeitos adversos , Aminofenóis/uso terapêutico , Benzodioxóis/efeitos adversos , Benzodioxóis/uso terapêutico , Agonistas dos Canais de Cloreto/efeitos adversos , Agonistas dos Canais de Cloreto/uso terapêutico , Fibrose Cística/tratamento farmacológico , Combinação de Medicamentos , Indóis/efeitos adversos , Indóis/uso terapêutico , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Piridinas/uso terapêutico , Piridinas/efeitos adversos , Quinolinas/uso terapêutico , Quinolinas/efeitos adversos , Transtornos do Sono-Vigília/induzido quimicamenteRESUMO
Liver-related side effects are a known complication of treatment with elexacaftor/tezacaftor/ivacaftor (ETI) for cystic fibrosis (CF). Gilbert's syndrome is caused by a genetic mutation that reduces activity of the enzyme UDP glucuronosyltransferase 1 polypeptide A1 (UGT1A1), causing elevated levels of unconjugated bilirubin in the blood and duodenal bile. The presence of Gilbert's syndrome and CF might represent additive risk factors for liver-related adverse events during ETI treatment. This case series describes six people with CF (pwCF) in whom previously unknown Gilbert's syndrome was unmasked after initiation of treatment with ETI. Although all patients had some level of hepatic dysfunction and/or elevated levels of bilirubin after initiation of ETI, the clinical course varied. Only one patient had to stop ETI therapy altogether, while the others were able to continue treatment (some at a reduced dosage and others at the full recommended daily dosage). All patients, even those using a lower dosage, experienced clinical benefit during ETI therapy. Gilbert's syndrome is not a contraindication for ETI therapy but may be mistaken for a risk factor for liver-related adverse events in pwCF. This is something that physicians need to be aware of in pwCF who show liver adverse events during ETI therapy.
Assuntos
Aminofenóis , Benzodioxóis , Fibrose Cística , Combinação de Medicamentos , Doença de Gilbert , Hiperbilirrubinemia , Indóis , Pirazóis , Piridinas , Quinolonas , Humanos , Doença de Gilbert/genética , Doença de Gilbert/tratamento farmacológico , Masculino , Aminofenóis/efeitos adversos , Aminofenóis/uso terapêutico , Feminino , Adulto , Fibrose Cística/tratamento farmacológico , Fibrose Cística/complicações , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Indóis/efeitos adversos , Benzodioxóis/efeitos adversos , Benzodioxóis/uso terapêutico , Quinolonas/efeitos adversos , Quinolonas/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Hiperbilirrubinemia/induzido quimicamente , Adulto Jovem , Pirróis/efeitos adversos , Adolescente , Glucuronosiltransferase/genética , Pirrolidinas , QuinolinasRESUMO
BACKGROUND & AIMS: Cystic Fibrosis (CF) liver disease progresses to liver failure requiring transplantation in about 3 % of patients, 0.7 % of CF patients are post liver transplant. The prognosis of CF has improved with the introduction of elexacaftor/tezacaftor/ivacaftor (ETI). Due to the paucity of data and concerns regarding interactions with immunosuppressive drug regimens, there is no general consensus on use of ETI post liver transplantation. The aim of this review is to report the safety and efficacy of ETI in CF patients who underwent liver transplantation. METHODS: A systematic review was conducted through MEDLINE/Pubmed and EMBASE databases. English-written articles reporting clinical data on liver transplanted CF patients treated with ETI were included. Article quality was evaluated using the Critical Appraisal Checklist for Case Reports. RESULTS: Twenty cases were retrieved from 6 reports. Temporary discontinuation and/or dose reduction due to elevated transaminases was required in 5 cases. ETI restarted on a reduced dose was tolerated in 3 out of 5 patients, 1 patient tolerated full dose. Tacrolimus dose change was required in 14 cases, in 1 case ETI was discontinued due to tacrolimus toxicity. Improvement in percentage predicted FEV1 was noted in 15/19 patients (median +17 %, range 8 %-38 %). CONCLUSIONS: In the majority of liver transplanted patients ETI is well tolerated, although adverse events and liver function abnormalities may occur. Close monitoring of liver function and tacrolimus level is warranted. Significant improvement in lung function after ETI initiation is confirmed, highlighting the importance of accessing this medication for this group of patients.
Assuntos
Aminofenóis , Benzodioxóis , Fibrose Cística , Indóis , Transplante de Fígado , Quinolonas , Humanos , Aminofenóis/uso terapêutico , Aminofenóis/efeitos adversos , Benzodioxóis/uso terapêutico , Benzodioxóis/efeitos adversos , Agonistas dos Canais de Cloreto/uso terapêutico , Agonistas dos Canais de Cloreto/efeitos adversos , Fibrose Cística/cirurgia , Fibrose Cística/tratamento farmacológico , Combinação de Medicamentos , Indóis/efeitos adversos , Indóis/uso terapêutico , Transplante de Fígado/métodos , Transplante de Fígado/efeitos adversos , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Piridinas/administração & dosagem , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Pirróis/uso terapêutico , Pirrolidinas , Quinolonas/uso terapêutico , Quinolonas/efeitos adversosAssuntos
Aminofenóis , Benzodioxóis , Creatina Quinase , Fibrose Cística , Combinação de Medicamentos , Indóis , Pirazóis , Rabdomiólise , Adolescente , Humanos , Aminofenóis/efeitos adversos , Aminofenóis/uso terapêutico , Benzodioxóis/efeitos adversos , Benzodioxóis/uso terapêutico , Creatina Quinase/sangue , Fibrose Cística/tratamento farmacológico , Fibrose Cística/complicações , Indóis/efeitos adversos , Pirazóis/efeitos adversos , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Pirróis/efeitos adversos , Pirrolidinas , Quinolinas/efeitos adversos , Quinolinas/uso terapêutico , Quinolonas/efeitos adversos , Quinolonas/uso terapêutico , Rabdomiólise/induzido quimicamente , Tiofenos/efeitos adversos , Tiofenos/uso terapêuticoRESUMO
INTRODUCTION: The efficacy and safety of elexacaftor/tezacaftor/ivacaftor (ETI) have been established in prospective clinical trials. Liver function test elevations were observed in a greater proportion of patients receiving ETI compared with placebo; however, the relatively small number of patients and short duration of study preclude detection of rare but clinically significant associations with drug-induced liver injury (DILI). To address this gap, we assessed the real-world risk of DILI associated with ETI through data mining of the FDA adverse event reporting system (FAERS). METHODS: Disproportionality analyses were conducted on FAERS data from the fourth quarter of 2019 through the third quarter of 2022. Comparative patient demographics, onset time and outcomes for ETI-DILI were also obtained. RESULTS: 452 reports of DILI associated with ETI were found, representing 2.1 % of all adverse event reports for ETI. All disproportionality measures were significant for ETI-DILI at p < 0.05; the reporting odds ratio (ROR) (2.82) was comparable to that of drugs classified by FDA as "Most-DILI concern". The most notable demographic finding was a male majority (5:4 male to female ratio) for ETI-DILI compared to a female majority (4:5 male to female ratio) for non ETI-DILI. Median ETI-DILI onset time was 50.5 days, and hospitalization was the second most common complication. CONCLUSION: Using FAERS data, ETI was found to be disproportionately associated with DILI. Future research is needed to investigate the hepatotoxic mechanisms and assess potential mitigation strategies for ETI-induced hepatotoxicity.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Aminofenóis , Benzodioxóis , Doença Hepática Induzida por Substâncias e Drogas , Combinação de Medicamentos , Indóis , Farmacovigilância , Piridinas , Quinolonas , United States Food and Drug Administration , Humanos , Masculino , Feminino , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Estados Unidos/epidemiologia , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Adulto , Indóis/efeitos adversos , Aminofenóis/efeitos adversos , Benzodioxóis/efeitos adversos , Piridinas/efeitos adversos , Quinolonas/efeitos adversos , Pessoa de Meia-Idade , Pirazóis/efeitos adversos , Fibrose Cística/tratamento farmacológico , Pirróis/efeitos adversos , Adolescente , Adulto Jovem , QuinolinasRESUMO
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.
Assuntos
Aminofenóis , Benzodioxóis , Fibrose Cística , Interações Medicamentosas , Imunossupressores , Indóis , Transplante de Rim , Transplante de Fígado , Quinolonas , Tacrolimo , Humanos , Fibrose Cística/cirurgia , Fibrose Cística/tratamento farmacológico , Tacrolimo/administração & dosagem , Tacrolimo/farmacocinética , Tacrolimo/efeitos adversos , Masculino , Feminino , Adulto , Benzodioxóis/efeitos adversos , Benzodioxóis/administração & dosagem , Benzodioxóis/uso terapêutico , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos , Quinolonas/farmacocinética , Transplante de Fígado/métodos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imunossupressores/farmacocinética , Transplante de Rim/efeitos adversos , Aminofenóis/administração & dosagem , Aminofenóis/efeitos adversos , Aminofenóis/farmacocinética , Aminofenóis/uso terapêutico , Indóis/administração & dosagem , Indóis/efeitos adversos , Indóis/farmacocinética , Pirazóis/farmacocinética , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Combinação de Medicamentos , Piridinas/administração & dosagem , Piridinas/farmacocinética , Piridinas/efeitos adversos , Pirróis/administração & dosagem , Pirróis/farmacocinética , Pirróis/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Quinolinas/farmacocinética , Adulto Jovem , Monitoramento de Medicamentos/métodos , PirrolidinasRESUMO
BACKGROUND: This single-center, retrospective study evaluated the effects of de-escalating cystic fibrosis (CF) supportive therapies in patients on elexacaftor/tezacaftor/ivacaftor (ETI). For many with CF, the clinical benefit of ETI exceeds that of supportive therapies. Therefore, we anticipated patients would desire to discontinue many of their supportive therapies, leading to the creation of a de-escalation algorithm. If patients were clinically improved and stable on ETI, CF supportive therapies could be de-escalated quarterly in accordance with the algorithm. METHODS: The primary objective was to assess non-inferiority of supportive therapies de-escalation by comparing the absolute change in percent predicted (ppFEV1) from baseline to month 1 versus the absolute change from baseline to month 12 after initiating ETI with patients serving as their own control. A chart review of patients initiated on ETI from September 2019 through December 2020 was conducted. Inclusion criteria included those six years and older with at least one copy of F508del. RESULTS: The study included 174 patients. The mean ppFEV1 at baseline, month 1, and month 12 was 67%, 78%, and 87% respectively. The mean difference in absolute change in ppFEV1 from baseline to month 1 compared to baseline to month 12 after the initiation of ETI was 1.53% (95% CI: -0.49 to 3.55) CONCLUSION: De-escalating supportive therapies for those on ETI was non-inferior to remaining on all supportive therapies. This suggests that medications may be able to be discontinued under the context of a de-escalation algorithm, which may decrease medication burden and cost and increase quality of life.
Assuntos
Fibrose Cística , Indóis , Pirazóis , Piridinas , Pirrolidinas , Quinolonas , Humanos , Fibrose Cística/diagnóstico , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Qualidade de Vida , Estudos Retrospectivos , Aminofenóis/efeitos adversos , Benzodioxóis/efeitos adversos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , MutaçãoAssuntos
Fibrose Cística , Indóis , Pirazóis , Piridinas , Pirrolidinas , Quinolonas , Criança , Humanos , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Óxido Nítrico , Aminofenóis , Benzodioxóis/efeitos adversos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Mutação , Agonistas dos Canais de CloretoRESUMO
Elexacator/tezacaftor/ivacaftor (ETI) has improved cystic fibrosis (CF) outcomes. A reduction in use of maintenance medication after its initiation has been reported. Seventy-one adult people with CF (PwCF) who are followed in three CF centers and completed one year of treatment with ETI were included in this study. Their use of inhaled dornase-α, colistin, tobramycin, aztreonam and levofloxacin during this period was compared with the corresponding use during one year without ETI, using the Medication Possession Ratio (MPR). MPR was significantly decreased after ETI initiation for dornase-α (67±35% vs 48±40%, p<0.001) and for all four inhaled antibiotics together (62±33% vs 41±37%, p<0.001). The findings of this multi-center, retrospective, study suggest that the initiation of ETI significantly leads to decrease in use of standard inhaled medication in PwCF. The significance of this finding in the course of the disease is yet to be investigated by larger prospective clinical trials.
Assuntos
Fibrose Cística , Indóis , Pirazóis , Piridinas , Pirrolidinas , Quinolonas , Adulto , Humanos , Fibrose Cística/diagnóstico , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Estudos Prospectivos , Estudos Retrospectivos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Mutação , Benzodioxóis/efeitos adversos , Aminofenóis/efeitos adversosAssuntos
Fibrose Cística , Indóis , Pirazóis , Piridinas , Pirrolidinas , Quinolonas , Adulto , Humanos , Fibrose Cística/complicações , Fibrose Cística/diagnóstico , Fibrose Cística/tratamento farmacológico , Sono , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Aminofenóis/efeitos adversos , Benzodioxóis/efeitos adversos , Mutação , Agonistas dos Canais de Cloreto/efeitos adversos , Combinação de MedicamentosRESUMO
BACKGROUND: The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (E/T/I) has been associated with substantial multisystem benefits for people with CF eligible for therapy. In a minority, tolerance has been limited by hepatic toxicity. It is unknown whether there may be particular risk factors for significant drug-induced elevation in transaminases. OBJECTIVE: We aimed to determine the cause of raised transaminases following the introduction of E/T/I, and whether E/T/I can safely be continued in some individuals with elevated transaminases. METHODS: At a large, single, adult CF centre, individuals with transaminases >3 × the upper limit of normal (ULN) since commencing E/T/I underwent clinical assessment to exclude known causes of raised transaminases. Where an alternative cause could not be identified, individuals were discussed with hepatology to advise on further investigations to establish aetiology in addition to calculation of the updated Roussel Uclaf Causality Assessment Method (RUCAM) score to assess causality grading of drug-induced liver injury (DILI) due to E/T/I, and to guide management of ongoing CFTR modulator therapy. RESULTS: Of 337 adults taking E/T/I for a median of 27 months, 19 (5.6%) had transaminases >3 × ULN. In 12 individuals, there was clear evidence of an aetiology unrelated to E/T/I (RUCAM scores -2 to 1 [excluded-unlikely]). Of the remaining cases, two had RUCAM scores in the 'possible' range and one had a RUCAM score in the 'probable' range. Liver biopsy was performed in four individuals, showing hepatic steatosis in one individual, normal histology in one individual, and hepatocyte necrosis suggestive of DILI in two individuals. E/T/I was suspended in those with hepatocyte necrosis, with one permanent discontinuation due to synthetic dysfunction. One individual with hepatocyte necrosis on histology was successfully re-established on E/T/I therapy. CONCLUSIONS: Alternative causes were identified in the majority of patients with clinically significant increases in transaminases following E/T/I, highlighting the importance of thorough investigation. Multidisciplinary assessment involving an experienced hepatologist is crucial in cases of diagnostic uncertainty or suggestion of significant DILI, as discontinuation of therapy can have significant consequences for individuals.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Fibrose Cística , Hepatopatias , Adulto , Humanos , Fibrose Cística/tratamento farmacológico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Aminofenóis/efeitos adversos , Benzodioxóis/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Transaminases/uso terapêutico , Necrose/induzido quimicamente , MutaçãoRESUMO
Risk of cardiovascular disease (CVD) may be changing in people with cystic fibrosis (pwCF) with widespread use of highly effective modulator therapy (HEMT). We performed a retrospective analysis of patients who had lipids checked before and after initiation of ivacaftor or elexacaftor/tezacaftor/ivacaftor. We hypothesized that HEMT negatively impacts lipids (total cholesterol [TC], low-density lipoprotein [LDL], high-density lipoprotein [HDL], TC/HDL ratio). 41 adult patients were included. Paired t-tests showed statistically significant increases in TC (mean difference 16.3 mg/dL, p = 0.007, n = 40), LDL (mean difference 17.1 mg/dL, p < 0.001, n = 35), and TC/HDL ratio (mean difference 0.40, p = 0.014, n = 39) after HEMT initiation. HDL was unchanged (mean difference -1.5 mg/dL, p = 0.69, n = 39). Linear mixed models showed CF liver disease was associated with significantly blunted changes in TC and LDL. Family history of CVD risk factors was associated with significantly accentuated increases in TC and LDL. These data suggest a role for more lipid screening in pwCF.
Assuntos
Doenças Cardiovasculares , Fibrose Cística , Adulto , Humanos , Fibrose Cística/complicações , Fibrose Cística/tratamento farmacológico , Estudos Retrospectivos , Aminofenóis/efeitos adversos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Lipoproteínas LDL , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Benzodioxóis/efeitos adversos , MutaçãoAssuntos
Fibrose Cística , Humanos , Fibrose Cística/tratamento farmacológico , Prevalência , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Aminofenóis/efeitos adversos , Benzodioxóis/efeitos adversos , Mutação , Combinação de Medicamentos , Agonistas dos Canais de Cloreto/efeitos adversosRESUMO
INTRODUCTION: Cystic fibrosis (CF) is the most frequent recessive autosomal disorder in the Caucasian population. It is caused by mutations that result in a deficient or dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Among CFTR modulators, potentiator compounds increase channel opening, whereas corrector compounds increase CFTR quantity in the cell surface. OBJECTIVE: To report real-life effects of a generic formulation of lumacaftor-ivacaftor use in patients with CF homozygous for the Phe508del CFTR mutation. PATIENTS AND METHODS: Clinical variables (body mass index [BMI], pulmonary exacerbations, sweat test, and pulmonary function) were analyzed in 30 CF patients homozygous for the Phe508del CFTR mutation, treated with lumacaftor-ivacaftor for 12 months, at the Respiratory Center of Hospital de Niños Ricardo Gutiérrez. These clinical variables were compared with those before the use of modulators. RESULTS: A total of 30 patients with CF homozygous for the Phe508del CFTR mutation receiving lumacaftor-ivacaftor therapy were included in this study. The median (interquartile range [IQR]) age at the start of treatment was 10.79 (7.08-14.05) years. Nineteen patients were male. Before treatment, median (IQR) sweat chloride concentration was 80 (72-92) mEq/L, and it had decreased to 74 (68-78) mEq/L (p = .05) 12 months after treatment. Median (IQR) BMI z-score improved from -0.33 (-0.86 to 0.21) to -0.13 (-0.66 to 0.54) (p = .003). A spirometry was performed in 28 of 30 patients. Median (IQR) ppFEV1 was 83.5 (71-91) before treatment and 86.5 (67-103) after treatment (p = .38), 73.3% of patients referred decreased sputum production and 40% reported improvement in their dyspnea at 12 months. Severe pulmonary exacerbations significantly decreased from 60% in the year before treatment, to 30% at 12 months after treatment (p = .037); 13 patients showed an improvement in their exacerbation rates, 2 showed an increased rate, and 15 showed no change. CONCLUSIONS: The use of a generic formulation of lumacaftor-ivacaftor in patients homozygous for the Phe508del CFTR mutation was associated with improvement in nutritional status and respiratory symptoms, and a significant reduction in severe pulmonary exacerbations.
Assuntos
Fibrose Cística , Humanos , Masculino , Criança , Adolescente , Feminino , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/uso terapêutico , Combinação de Medicamentos , Aminofenóis , Aminopiridinas , Benzodioxóis/efeitos adversos , MutaçãoRESUMO
BACKGROUND: While elexacaftor/tezacaftor/ivacaftor (ETI) has improved the pulmonary health of many people with cystic fibrosis (PwCF), less is known about ETI effectiveness for extra-pulmonary manifestations, including fat-soluble vitamin malabsorption. This study aims to evaluate ETI's impact on vitamin A, D, E, and international normalized ratio (INR, an indirect marker for Vitamin K) serum levels. METHODS: Retrospective cohort study of PwCF ≥12 years receiving ETI. Vitamin levels up to four years preceding and up to two years following ETI initiation were collected. Pairwise comparisons of vitamin levels pre/post-ETI initiation were made using Wilcoxon signed rank and McNemar's tests. Linear mixed effect models were used to regress vitamin levels on time since starting ETI, ETI use (yes/no), the interaction between time and ETI use, and age. RESULTS: Two hundred and sixty-four participants met study inclusion, and 169 (64%) had post-ETI initiation vitamin levels. Median vitamin A levels increased from 422.0 to 471.0 mcg/L (p < 0.001), median vitamin D levels increased from 28.5 to 30.8 ng/mL (p = 0.003), and there were no significant changes in median vitamin E or INR. Vitamin A levels rose at a rate of 40.7 mcg/L/year (CI 11.3, 70.2) after ETI start. CONCLUSIONS: ETI initiation is associated with increased median vitamin A and vitamin D levels, but no change in median vitamin E or INR levels. Ongoing monitoring of vitamin levels after ETI initiation is needed to screen for potential deficiencies and toxicities, particularly in light of case reports of hypervitaminosis A following ETI initiation.
Assuntos
Fibrose Cística , Vitamina A , Humanos , Fibrose Cística/complicações , Fibrose Cística/diagnóstico , Fibrose Cística/tratamento farmacológico , Estudos Retrospectivos , Vitaminas , Vitamina D , Vitamina E , Regulador de Condutância Transmembrana em Fibrose Cística , Aminofenóis/efeitos adversos , Benzodioxóis/efeitos adversos , MutaçãoRESUMO
BACKGROUND: Elexacaftor/Tezacaftor/Ivacaftor (ETI) modulator therapy is often associated with increased body mass index (BMI) in people with cystic fibrosis (CF). This is thought to reflect improved clinical stability and increased appetite and nutritional intake. We explored the change in BMI and nutritional intake following ETI modulator therapy in adults with CF. METHODS: Dietary intake, measured with myfood24®, and BMI were collected from adults with CF at baseline and follow-up as part of an observational study. Changes in BMI and nutritional intake in participants who commenced ETI therapy between time points were assessed. To contextualize findings, we also assessed changes in BMI and nutritional intake between study points in a group on no modulators. RESULTS: In the pre and post ETI threapy group (n = 40), BMI significantly increased from 23.0 kg/m2 (IQR 21.4, 25.3) at baseline to 24.6 kg/m2 (IQR 23.0, 26.7) at follow-up (p<0.001), with a median of 68 weeks between time points (range 20-94 weeks) and median duration of ETI therapy was 23 weeks (range 7-72 weeks). There was a significant decrease in energy intake from 2551 kcal/day (IQR 2107, 3115) to 2153 kcal/day (IQR 1648, 2606), p<0.001. In the no modulator group (n = 10), BMI and energy intake did not significantly change between time points (p>0.05), a median of 28 weeks apart (range 20-76 weeks). CONCLUSIONS: These findings tentatively suggest that the increase in BMI with ETI therapy may not simply be attributable to an increase in oral intake. Further exploration into the underlying aetiology of weight gain with ETI therapy is needed.
Assuntos
Fibrose Cística , Adulto , Humanos , Índice de Massa Corporal , Fibrose Cística/diagnóstico , Fibrose Cística/tratamento farmacológico , Ingestão de Alimentos , Regulador de Condutância Transmembrana em Fibrose Cística , Mutação , Benzodioxóis/efeitos adversos , Aminofenóis/efeitos adversosAssuntos
Fibrose Cística , Doença de Gilbert , Humanos , Fibrose Cística/complicações , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Doença de Gilbert/diagnóstico , Doença de Gilbert/tratamento farmacológico , Doença de Gilbert/genética , Hiperbilirrubinemia , Aminofenóis/efeitos adversos , Benzodioxóis/efeitos adversos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Mutação , Agonistas dos Canais de Cloreto/efeitos adversos , Combinação de MedicamentosRESUMO
BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) has been associated with unprecedented clinical improvements, transforming the management of cystic fibrosis (CF). However, side effects with implications for safety and well-being have been reported, including neuropsychiatric changes. This study aimed to better characterize the emerging positive and negative impacts of ETI. METHODS: The Cystic Fibrosis Foundation's Mental Health Advisory Committee distributed a 26-item survey to US CF care teams to assess clinician observations of patient-reported experiences with ETI. Survey responses measured the prevalence of these effects in five domains: (1) positive physical and psychological effects, (2) sleep difficulties, (3) cognitive difficulties, (4) worsening mental health, and (5) concerns about the future and finances. RESULTS: Seventy-five healthcare providers responded from a pediatric, adult, and combined centers. Positive physical effects of ETI and increased optimism were reported in the upper quartiles (50%-100%) and rated as having a significant impact on daily functioning. Sleep and cognitive difficulties were reported in 1%-24%, with slight impacts on functioning, and psychological symptoms (e.g., increased stress, depression, anxiety) and new psychiatric medications were reported in 1%-24%, with moderate impacts. Concerns about the future were reported in 1%-24%, with minimal impacts. CONCLUSION: Across US centers, providers most often observed positive physical effects of ETI. However, a variety of negative side effects were also reported, including sleep disruptions and worsening psychological functioning, which should be systematically monitored by CF teams. These national-level data are a first step in evaluating the prevalence and consequences of these side effects and can directly inform future studies.
Assuntos
Fibrose Cística , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Adulto , Humanos , Criança , Fibrose Cística/tratamento farmacológico , Pessoal de Saúde , Regulador de Condutância Transmembrana em Fibrose Cística , Aminofenóis/efeitos adversos , Benzodioxóis/efeitos adversos , MutaçãoRESUMO
Rationale: A 24-week, phase 3, open-label study showed elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was safe and efficacious in children aged 6-11 years with cystic fibrosis (CF) and one or more F508del-CFTR alleles. Objectives: To assess long-term safety and efficacy of ELX/TEZ/IVA in children who completed the pivotal 24-week phase 3 trial. Methods: In this phase 3, two-part (part A and part B), open-label extension study, children aged ⩾6 years with CF heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) or homozygous for F508del (F/F genotype) who completed the 24-week parent study received ELX/TEZ/IVA based on weight. Children weighing <30 kg received ELX 100 mg once daily/TEZ 50 mg once daily/IVA 75 mg every 12 hours, whereas children weighing ⩾30 kg received ELX 200 mg once daily/TEZ 100 mg once daily/IVA 150 mg every 12 hours (adult dose). The 96-week analysis of part A of this extension study is reported here. Measurements and Main Results: Sixty-four children (F/MF genotypes, n = 36; F/F genotype, n = 28) were enrolled and received one or more doses of ELX/TEZ/IVA. Mean (SD) period of exposure to ELX/TEZ/IVA was 93.9 (11.1) weeks. The primary endpoint was safety and tolerability. Adverse events and serious adverse events were consistent with common manifestations of CF disease. Overall, exposure-adjusted rates of adverse events and serious adverse events (407.74 and 4.72 events per 100 patient-years) were lower than in the parent study (987.04 and 8.68 events per 100 patient-years). One child (1.6%) had an adverse event of aggression that was moderate in severity and resolved after study drug discontinuation. From parent study baseline at Week 96 of this extension study, the mean percent predicted FEV1 increased (11.2 [95% confidence interval (CI), 8.3 to 14.2] percentage points), sweat chloride concentration decreased (-62.3 [95% CI, -65.9 to -58.8] mmol/L), Cystic Fibrosis Questionnaire-Revised respiratory domain score increased (13.3 [95% CI, 11.4 to 15.1] points), and lung clearance index 2.5 decreased (-2.00 [95% CI, -2.45 to -1.55] units). Increases in growth parameters were also observed. The estimated pulmonary exacerbation rate per 48 weeks was 0.04. The annualized rate of change in percent predicted FEV1 was 0.51 (95% CI, -0.73 to 1.75) percentage points per year. Conclusions: ELX/TEZ/IVA continued to be generally safe and well tolerated in children aged ⩾6 years through an additional 96 weeks of treatment. Improvements in lung function, respiratory symptoms, and CFTR function observed in the parent study were maintained. These results demonstrate the favorable long-term safety profile and durable clinical benefits of ELX/TEZ/IVA in this pediatric population. Clinical trial registered with www.clinicaltrials.gov (NCT04183790).
Assuntos
Fibrose Cística , Adulto , Criança , Humanos , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Fibrose Cística/diagnóstico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/uso terapêutico , Alelos , Agonistas dos Canais de Cloreto/uso terapêutico , Aminofenóis/efeitos adversos , Benzodioxóis/efeitos adversos , MutaçãoRESUMO
OBJECTIVE: To assess the feasibility of enrolling people with CF (pwCF) taking the CFTR modulator elexacaftor/tezacaftor/ivacaftor (ETI) in clinical trials of a new modulator. METHODS: PwCF receiving ETI at CHEC-SC study (NCT03350828) enrollment were surveyed for interest in 2-week to 6-month placebo- (PC) and active-comparator (AC) modulator studies. Those taking inhaled antimicrobials (inhABX) were surveyed for interest in PC inhABX studies. RESULTS: Of 1791 respondents, 75% [95% CI 73, 77] would enroll in a 2-week PC modulator study versus 51% [49, 54] for a 6-month study; 82% [81, 84] and 63% [61, 65] would enroll in 2-week and 6 month AC studies; 77% [74, 80] of 551 taking inhABX would enroll in a 2-week PC inhABX study versus 59% [55, 63] for a 6-month study. Previous clinical trial experience increased willingness. CONCLUSIONS: Study designs will affect feasibility of future clinical trials of new modulators and inhABX in people receiving ETI.