Elexacaftor‐tezacaftor‐ivacaftor overdose in an adolescent female with cystic fibrosis

Lyman, Benjamin C.; Seay, Jessica; Contreary, Casey; Savant, Adrienne P.; Dell, Mary Lynn; Hescock, George

doi:10.1002/ppul.26116

Cited by 4 publications

(5 citation statements)

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“…The objective changes in lung function and nutritional status have been clearly documented, leading to a dramatic shift in optimism and increased hopes for the future for those taking ETI. However, there is also evidence that improved CFTR modulation can lead to changes in sleep, cognition, and psychological functioning, which negatively affect daily functioning and may require alterations in the dosing of ETI or discontinuation of this medication 9–12,25 . Across these US centers, sleep difficulties, cognitive fogginess, new onset depression and/or anxiety, and worsening of existing psychological symptoms were the side effects most commonly associated with impacts on daily functioning and changes in ETI prescriptions.…”

Section: Discussionmentioning

confidence: 99%

“…However, there is also evidence that improved CFTR modulation can lead to changes in sleep, cognition, and psychological functioning, which negatively affect daily functioning and may require alterations in the dosing of ETI or discontinuation of this medication. [9][10][11][12]25 Across these US centers, sleep difficulties, cognitive fogginess, new onset depression and/or anxiety, and worsening of existing psychological symptoms were the side effects most commonly associated with impacts on daily functioning and changes in ETI prescriptions. These results provide guidance on the specific symptoms that should be measured and followed more precisely in a multisite, longitudinal study, and point to key areas of uncertainty that may lead to psychological distress (e.g., career planning, financial stressors).…”

Section: Limitationsmentioning

confidence: 99%

“…To date these negative side‐effects have been reported in single‐center studies, case reports, and case series 5,6,9–12,23,24 ; however, larger epidemiologic studies are needed to better characterize these relationships. Regardless of etiology, an understanding of the intersection of mental health and CFTR modulator use remains important when psychiatric management is indicated 7,25 …”

Section: Introductionmentioning

confidence: 99%

“…Regardless of etiology, an understanding of the intersection of mental health and CFTR modulator use remains important when psychiatric management is indicated. 7,25 Second, the psychological impact of initiating a CFTR modulator can be complex. 7,26,27 Qualitative work has identified positive themes (stability, hope, new goals), as well as the uncertainties associated with shifts in identity, the CF treatment regimen, and perceptions of the future.…”

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confidence: 99%

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Positive and negative impacts of elexacaftor/tezacaftor/ivacaftor: Healthcare providers' observations across US centers

Bathgate

Muther

Georgiopoulos

et al. 2023

Pediatric Pulmonology

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BackgroundElexacaftor/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.MethodsThe 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.ResultsSeventy‐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.ConclusionAcross 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.

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Section: Discussionmentioning

confidence: 99%

Section: Limitationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Positive and negative impacts of elexacaftor/tezacaftor/ivacaftor: Healthcare providers' observations across US centers

Bathgate

Muther

Georgiopoulos

et al. 2023

Pediatric Pulmonology

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“…However, ETI is also not a feasible option for some genotype-appropriate PwCF. Despite improvements in physical health, a minority of PwCF initiating CFTR modulators have experienced clinically significant neuropsychiatric adverse effects (AEs), including worsening mood, cognition, anxiety, and sleep, and emergent suicidal thoughts or behavior [ 5 , 6 ▪▪ , 7 ▪ , 8 , 9 , 10 ▪ , 11 ▪ ]. These symptoms can be so profound that some PwCF make the difficult decision to stop using a medication that would reduce their physical suffering and extend their life.…”

Section: Introductionmentioning

confidence: 99%

Neuropsychiatric adverse effects from CFTR modulators deserve a serious research effort

VanElzakker,

Tillman,

Yonker

et al. 2023

Current Opinion in Pulmonary Medicine

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Purpose of review This review highlights the problem of neuropsychiatric adverse effects (AEs) associated with elexacaftor/tezacaftor/ivacaftor (ETI), current suboptimal mitigation approaches, a novel testable mechanistic hypothesis, and potential solutions requiring further research. Recent findings Studies show that a minority of persons with cystic fibrosis (PwCF) initiating cystic fibrosis transmembrane conductance regulator (CFTR) modulators experience neuropsychiatric AEs including worsening mood, cognition, anxiety, sleep, and suicidality. The GABA-A receptor is a ligand-gated chloride channel, and magnetic resonance spectroscopy neuroimaging studies have shown that reduced GABA expression in rostral anterior cingulate cortex is associated with anxiety and depression. Recent research details the impact of peripheral inflammation and the gut-brain axis on central neuroinflammation. Plasma ETI concentrations and sweat chloride have been evaluated in small studies of neuropsychiatric AEs but not validated to guide dose titration or correlated with pharmacogenomic variants or safety/efficacy. Summary Although ETI is well tolerated by most PwCF, some experience debilitating neuropsychiatric AEs. In some cases, these AEs may be driven by modulation of CFTR and chloride transport within the brain. Understanding biological mechanisms is a critical next step in identifying which PwCF are likely to experience AEs, and in developing evidence-based strategies to mitigate them, while retaining modulator efficacy.

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Elexacaftor/ivacaftor/tezacaftor overdose

2023

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Elexacaftor‐tezacaftor‐ivacaftor overdose in an adolescent female with cystic fibrosis

Cited by 4 publications

References 3 publications

Positive and negative impacts of elexacaftor/tezacaftor/ivacaftor: Healthcare providers' observations across US centers

Positive and negative impacts of elexacaftor/tezacaftor/ivacaftor: Healthcare providers' observations across US centers

Neuropsychiatric adverse effects from CFTR modulators deserve a serious research effort

Elexacaftor/ivacaftor/tezacaftor overdose

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