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

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.
Competing Interests: Declaration of Competing Interest S.M.R. serves as investigator and consultant to Vertex Pharmaceuticals, the manufacturer of ivacaftor, ivacaftor/lumacaftor, and ivacaftor/tezacaftor on CF clinical trials. J.S.G. and E.P.A. participated in clinical studies independent of Vertex Pharmaceuticals to evaluate the CFTR modulators described here. All other authors declare no conflicts of interest.
(Copyright © 2020. Published by Elsevier B.V.)