Background: Recent studies revealed that some people with cystic fibrosis (pwCF) receiving the full dose of Elexacaftor/Tezacaftor/Ivacaftor (ETI) experience adverse events (AEs), leading to discontinuation or dose adjustments of their modulator treatment. We aimed to investigate if pwCF who experienced AEs had high exposure to ETI, and to what extent dose reduction resulted in changes in exposure, side effects and efficacy.
Method: This retrospective case series presents ETI exposure in pwCF who required ETI dose reduction due to AEs. ETI exposure was measured by minimal concentration (Cmin) levels, while sweat chloride concentration (SCC) was used to assess efficacy. AEs were graded using the common terminology criteria for AEs. Ten pwCF who experienced AEs during ETI treatment were included in the study.
Results: The mean Cmin levels at the full ETI dose were 10.1 mg/L for elexacaftor, 4.2 mg/L for tezacaftor, and 1.2 mg/L for ivacaftor. These values exceed the mean Cmin values from the registration studies, which are 5.5 mg/L for elexacaftor, 2.1 mg/L for tezacaftor, and 0.8 mg/L for ivacaftor. The most frequently reported AEs were psychiatric and nervous system disorders. In all ten pwCF, an improvement of AEs was noted after dose reduction. The mean SCC measured on the full ETI dose was 38 mmol/L. Post dose reduction, the mean SCC was 44 mmol/L.
Conclusion: This study suggest that AEs of ETI in most cases could be related to elevated exposure levels. Dose reduction decreases ETI exposure and AEs while maintaining efficacy as determined with sweat chloride levels.
Keywords: Adverse events; Cystic fibrosis; Dose reduction; Drug concentration levels; Elexacaftor/tezacaftor/ivacaftor; Pharmacology.
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