A bioassay using intestinal organoids to measure CFTR modulators in human plasma

R Dekkers; L A W Vijftigschild; A M Vonk; E Kruisselbrink; K M de Winter-de Groot; H M Janssens; C K van der Ent; J M Beekman

doi:10.1016/j.jcf.2014.10.007

A bioassay using intestinal organoids to measure CFTR modulators in human plasma

J Cyst Fibros. 2015 Mar;14(2):178-81. doi: 10.1016/j.jcf.2014.10.007. Epub 2014 Nov 6.

Authors

R Dekkers¹, L A W Vijftigschild¹, A M Vonk¹, E Kruisselbrink¹, K M de Winter-de Groot², H M Janssens³, C K van der Ent², J M Beekman⁴

Affiliations

¹ Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Center, Utrecht, The Netherlands.
² Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center, Utrecht, The Netherlands.
³ Department of Pediatric Pulmonology, Erasmus University Medical Center/Sophia Children's Hospital, Rotterdam, The Netherlands.
⁴ Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Center, Utrecht, The Netherlands; Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center, Utrecht, The Netherlands. Electronic address: [email protected].

PMID: 25467948
DOI: 10.1016/j.jcf.2014.10.007

Abstract

Treatment efficacies of drugs depend on patient-specific pharmacokinetic and pharmacodynamic properties. Here, we developed an assay to measure functional levels of the CFTR potentiator VX-770 in human plasma and observed that VX-770 in plasma from different donors induced variable CFTR function in intestinal organoids. This assay can help to understand variability in treatment response to CFTR potentiators by functionally modeling individual pharmacokinetics.

Keywords: CFTR; Intestinal organoids; Personalized medicine; Pharmacokinetics; VX-770.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aminophenols / pharmacokinetics*
Antimutagenic Agents / pharmacokinetics
Biological Assay
Cystic Fibrosis Transmembrane Conductance Regulator* / genetics
Cystic Fibrosis Transmembrane Conductance Regulator* / metabolism
Cystic Fibrosis* / drug therapy
Cystic Fibrosis* / genetics
Cystic Fibrosis* / physiopathology
Drug Monitoring / methods
Humans
Intestinal Mucosa* / metabolism
Intestines* / pathology
Mutation / drug effects
Organoids* / drug effects
Organoids* / metabolism
Quinolones / pharmacokinetics*
Treatment Outcome

Substances

Aminophenols
Antimutagenic Agents
Quinolones
Cystic Fibrosis Transmembrane Conductance Regulator
ivacaftor