Variable cellular ivacaftor concentrations in people with cystic fibrosis on modulator therapy

• Published in: Journal of cystic fibrosis 2020-09, Vol.19 (5), p.742-745
• Main Authors: Guimbellot, Jennifer S., Ryan, Kevin J., Anderson, Justin D., Liu, Zhongyu, Kersh, Latona, Esther, Charles R., Rowe, Steven M., Acosta, Edward P.
• Format: Article
• Language: English
• Subjects: CFTR; Drug concentrations; Ivacaftor
• ISSN: 1569-1993; 1873-5010
• DOI: 10.1016/j.jcf.2020.01.011

•An LC-MS/MS assay was developed to quantitate CFTR modulators in epithelial cells and in plasma for clinical purposes and mechanistic studies.•This pilot study shows that the concentration of ivacaftor reaching epithelial cells may differ from what might be expected based on plasma concentrations.•In this study, the concentrations of ivacaftor measured from cells approach those used in vitro studies showing detrimental effects on CFTR restoration and the plasma membrane. The development of CFTR modulators has transformed the care of patients with cystic fibrosis (CF). Although the clinical efficacy of modulators depends on their concentrations in target tissues, the pharmacokinetic properties of these drugs in epithelia are not utilized to guide patient care. We developed assays to quantitate ivacaftor in cells and plasma from patients on modulator therapy, and our analyses revealed that cellular ivacaftor concentrations differ from plasma concentrations measured concurrently, with evidence of in vivo accumulation of ivacaftor in the cells of patients. While the nature of this study is exploratory and limited by a small number of patients, these findings suggest that techniques to measure modulator concentrations in vivo will be essential to interpreting their clinical impact, particularly given the evidence that ivacaftor concentrations influence the activity and stability of restored CFTR protein.