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Characterizing CFTR modulated sweat chloride response across the cf population: Initial results from the CHEC-SC study.

Characterizing CFTR modulated sweat chloride response across the cf population: Initial results from the CHEC-SC study.

Authors :
Mayer-Hamblett, N
Zemanick, ET
Odem-Davis, K
VanDevanter, D
Warden, M
Rowe, SM
Young, J
Konstan, MW
for-the-CHEC-SC-Study-Group
Source :
Journal of Cystic Fibrosis. Jan2023, Vol. 22 Issue 1, p79-88. 10p.
Publication Year :
2023

Abstract

• Modulator-induced sweat chloride (SC) responses across the CF population were consistent with those reported from prior clinical studies. • Variation in SC response to a single highly effective modulator, ivacaftor, was evident across individuals with differing mutation profiles; in vivo SC responses correlated with in vitro ivacaftor modulated CFTR functional responses. • With the exception of the cohort of F508del homozygous participants established on tezacaftor/ivacaftor, there were notable shifts in the proportion of participants with SC levels <60mmol/L across modulators and genotype groups independent of the magnitude of average SC change observed pre- to post- modulator. • Female as compared to male sex at birth was not strongly associated with greater SC response to CFTR modulators as has been identified in prior studies. CHEC-SC is an ongoing epidemiologic study characterizing modulator-induced sweat chloride (SC) responses across the CF population, with interim results available prior to the availability of triple combination modulator therapy. Eligible participants had been prescribed a modulator for ≥90 days with re-enrollment allowed upon establishment of a new modulator. Pre-modulator SC values were obtained from chart review; post-modulator sweat was collected and analyzed locally. SC changes were descriptively summarized with biologic sex effects adjusted for age, weight, and CFTR genotype. Heterogeneity in ivacaftor SC response was characterized in relation to published CFTR functional responses. 1848 participants provided 2004 SC measurements, 26.2% on ivacaftor, 39.1% on lumacaftor/ivacaftor, and 34.7% on tezacaftor/ivacaftor. Average SC changes for all modulators were consistent with those reported in previous clinical studies, with greater variation in SC response observed among rarer mutations and notable shifts in the proportion with SC <60mmol/L independent of the magnitude of SC change. Ivacaftor induced in vitro CFTR functional change was significantly correlated with ivacaftor-modulated SC response (Pearson correlation= ‒0.52, 95% CI: ‒0.773, ‒0.129). Average SC change from ivacaftor to tezacaftor/ivacaftor was ‒4.9 mmol/L (n=17,95% CI:‒9.3, ‒0.5) and differed from those switching from lumacaftor/ivacaftor (10.0 mmol/L, n=139, 95% CI:7.8,12.3). Sex at birth was not associated with SC response. CHEC-SC is the largest study characterizing modulator-induced SC changes across the CF population. There was a strong association between ivacaftor induced in vitro CFTR function and SC response across a genotypically heterogenous cohort. Biological sex was not associated with SC response. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
15691993
Volume :
22
Issue :
1
Database :
Academic Search Index
Journal :
Journal of Cystic Fibrosis
Publication Type :
Academic Journal
Accession number :
162362290
Full Text :
https://doi.org/10.1016/j.jcf.2022.07.008