Preliminary evidence for sustained efficacy of CFTR modulator therapy with concomitant rifabutin administration

Eunjin Hong; Sarah M Parsons; Laura Sass; Cynthia Epstein; Lynn Chan; Claire Brown; Patricia H Eshaghian; Paul M Beringer

doi:10.1016/j.jcf.2023.11.015

Preliminary evidence for sustained efficacy of CFTR modulator therapy with concomitant rifabutin administration

J Cyst Fibros. 2023 Nov 30:S1569-1993(23)01721-6. doi: 10.1016/j.jcf.2023.11.015. Online ahead of print.

Authors

Eunjin Hong¹, Sarah M Parsons², Laura Sass², Cynthia Epstein², Lynn Chan³, Claire Brown⁴, Patricia H Eshaghian⁵, Paul M Beringer⁶

Affiliations

¹ Department of Clinical Pharmacy, Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, 1985 Zonal Ave, Los Angeles, CA 90033, United States; College of Pharmacy, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, South Korea.
² Children's Hospital of The King's Daughters, 601 Children's Ln, Norfolk, VA 23507, United States.
³ Department of Pharmaceutical Services, University of California Los Angeles, 757 Westwood Plaza, Los Angeles, CA 90095, United States.
⁴ Division of Infectious Diseases, University of California Los Angeles, 757 Westwood Plaza, Los Angeles, CA 90095, United States.
⁵ Division of Pulmonary and Critical Care Medicine, University of California Los Angeles, 1260 15(th) St #600, Santa Monica, CA 90404, United States.
⁶ Department of Clinical Pharmacy, Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, 1985 Zonal Ave, Los Angeles, CA 90033, United States; USC Anton Yelchin CF Clinic, 1510 San Pablo St, Los Angeles, CA 90033, United States. Electronic address: beringer@usc.edu.

PMID: 38036321
DOI: 10.1016/j.jcf.2023.11.015

Abstract

The concomitant use of elexacaftor/tezacaftor/ivacaftor (ETI) and strong CYP3A inducers including rifampin and rifabutin is not recommended due to the risk of drug-drug interactions (DDI). This presents a significant challenge to the treatment of non-tuberculous mycobacteria precluding the first line treatment. While rifabutin induces CYP3A activity, its effect appears to be moderate compared to rifampin. In this study, we investigated three cases in which concomitant use of rifabutin and CFTR modulators (ETI or ivacaftor monotherapy) was used, and these cases suggest that addition of rifabutin did not compromise the efficacy of ETI or ivacaftor as evidenced by pulmonary function and sweat chloride testing. A full physiologically based pharmacokinetic model predicted lung concentrations of ETI upon rifabutin coadministration to exceed the half-maximal effective concentrations (EC₅₀) determined from chloride transport in phe508del human bronchial epithelial cells. This study provides preliminary evidence in support of the use of rifabutin in patients receiving ETI.

Keywords: Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy; Drug-drug interaction (DDI); Non-tuberculous mycobacteria (NTM); Physiologically based pharmacokinetic (PBPK); Rifabutin.