Individualized approach to elexacaftor/tezacaftor/ivacaftor dosing in cystic fibrosis, in response to self-reported anxiety and neurocognitive adverse events: A case series

Abstract

The prevalence of mental health disorders is high among people with Cystic Fibrosis. The psychological symptoms in CF are associated with poor adherence, worse treatment outcomes, and greater health utilization/cost. Mental health and neurocognitive Adverse Events (AEs) have been reported with all available Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators in small groups of patients. We report our experience with a dose reduction strategy in 10 of our patients on elexacaftor/tezacaftor/ivacaftor (7.9% of total number of patients) who self-reported developing intense anxiety, irritability, sleep disturbance and/or mental slowness after initiation of full dose treatment. Standard dose elexacaftor/tezacaftor/ivacaftor resulted in 14.3 points improvement in mean Percent Predicted Forced Expiratory Volume in 1 s (ppFEV1), and a mean difference in sweat chloride of −39.3 mmol/L. We initially discontinued and/or reduced therapy according to the AEs severity, with a subsequent planned dose escalation every 4–6 weeks guided by sustainability of clinical effectiveness, absence of AEs recurrence, and patients’ preferences. Clinical parameters including lung function and sweat chloride were monitored for up to 12 weeks to assess ongoing clinical response to the reduced dose regimen. Dose reduction resulted in resolution of self-reported mental/psychological AEs, without loss of clinical effectiveness (ppFEV1 was 80.7% on standard dose, and 83.4% at 12 weeks on reduced dose; sweat chloride was 33.4 and 34 mmol/L on standard and reduced dose, respectively). Furthermore, in a subgroup of patients who completed 24 weeks of the reduced dose regimen, repeat low dose Computed Tomography imaging showed a significant response when compared to pre-initiation of elexacaftor/tezacaftor/ivacaftor.

Paediatric Thoracic Imaging in Cystic Fibrosis in the Era of Cystic Fibrosis Transmembrane Conductance Regulator Modulation

“…Another consideration is that there have been cases in adults where doses of CFTR modulators have been reduced in response to side effects, particularly anxiety and neurocognitive effects. The evidence to date has shown lesser side effects in response to dose reduction with ongoing clinical benefit, measured with spirometry and sweat chloride levels [128][129][130]. It follows that there may be a role for imaging surveillance in children who may require CFTR modulator dose reduction and are unable to complete spirometry or in those with normal spirometry.…”

Highly effective cystic fibrosis transmembrane conductance (regulator) modulator therapy: shifting the curve for most while leaving some further behind

“…Additionally, there is CFTR expression in the brain and ivacaftor binds to neurotransmitter receptors [24]. The neuropsychiatric effects have improved shortly after modulator therapy was reduced or stopped, suggesting a direct relationship to HEMT [25]. The importance of mental health in CF has been reflected by a nearly universal implementation of mental screening in US CF care centers [26].…”

Neuropsychiatric adverse effects from CFTR modulators deserve a serious research effort

“…PwCF, family caregivers and CF care teams may thus be reluctant to employ this strategy or differ in opinion about its risk/benefit ratio. Additionally, in some cases neuropsychiatric AEs continue unless ETI is discontinued or psychopharmacologic therapies are employed [ 6 ▪▪ , 11 ▪ , 70 ▪ ].…”

“…In a case series of ten PwCF with new neuropsychiatric symptoms after ETI initiation, including anxiety, irritability, sleep disturbance and/or mental slowness, one discontinued ETI and resumed ivacaftor therapy. Nine underwent dose reduction, using a standardized protocol with serial sweat chloride measurement [ 70 ▪ ]. Mean sweat chlorides were similar on the standard dose (33.4 mmol/L) and the reduced dose (34 mmol/L).…”

“…Mean sweat chlorides were similar on the standard dose (33.4 mmol/L) and the reduced dose (34 mmol/L). While six of the nine had complete resolution of symptoms with dose reduction, three had only partial resolution [ 70 ▪ ]. Sweat chloride concentrations decrease with ETI treatment, and data show a direct relationship between improved pulmonary function and sweat chloride concentrations [ 71 ], but to our knowledge neither ETI concentrations nor sweat chloride concentrations have been associated with the occurrence of AEs [ 72 ].…”