Phase 1 Study to Assess the Safety and Pharmacokinetics of Elexacaftor/Tezacaftor/Ivacaftor in Subjects Without Cystic Fibrosis With Moderate Hepatic Impairment.

Abstract

BACKGROUND AND OBJECTIVE:

Elexacaftor/tezacaftor/ivacaftor is highly effective in treating people with cystic fibrosis (pwCF) who have ≥ 1 responsive mutation. Liver disease occurs in approximately 10%-20% of pwCF. The objective of this study was to assess the safety and pharmacokinetics of elexacaftor/tezacaftor/ivacaftor in people with moderate hepatic impairment, which is necessary to inform on its use and guide dosing recommendations.

METHODS:

The safety and pharmacokinetics of elexacaftor/tezacaftor/ivacaftor were evaluated in subjects without CF with moderate hepatic impairment versus matched healthy controls. Twenty-two subjects (11 with moderate hepatic impairment and 11 healthy subjects) received half the standard adult daily dose of elexacaftor/tezacaftor/ivacaftor (elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 150 mg) orally for 10 days.

RESULTS:

Elexacaftor/tezacaftor/ivacaftor was safe and well tolerated in subjects with moderate hepatic impairment and healthy controls. On day 10, the mean values of the area under the curve during the dosing interval (AUCτ) for total (bound and unbound) elexacaftor and its major active metabolite M23-elexacaftor were increased 1.25-fold (95% CI 1.01, 1.54) and 1.73-fold (95% CI 1.27, 2.35), respectively, in subjects with moderate hepatic impairment compared with matched healthy subjects. The mean values of AUCτ for ivacaftor and tezacaftor were increased 1.50-fold (95% CI 1.09, 2.06) and 1.20-fold (95% CI 1.00, 1.43), respectively, while the mean value of AUCτ for the active metabolite M1-tezacaftor was 1.29-fold lower [ratio of moderate hepatic impairment to healthy subjects (95% CI): 0.778 (0.655, 0.924)] in subjects with moderate hepatic impairment.

CONCLUSIONS:

A dose reduction of elexacaftor/tezacaftor/ivacaftor is warranted in people with moderate hepatic impairment. (Trial registry number 2018-002570-40; registered 2 July 2018.).

• Authors: Lakshmi Viswanathan, Eric Bachman, Simon Tian, Neil Ahluwalia, Yaohua Zhang, Harold S Bernstein, Paul Panorchan
• Journal: European journal of drug metabolism and pharmacokinetics (Eur J Drug Metab Pharmacokinet) Vol. 47 Issue 6 Pg. 817-825 (Nov 2022) ISSN: 2107-0180 [Electronic] France
• PMID: 36036885 (Publication Type: Clinical Trial, Phase I, Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• ivacaftor
• tezacaftor
• elexacaftor
• Cystic Fibrosis Transmembrane Conductance Regulator

Topics

• Adult
• Humans
• Cystic Fibrosis (drug therapy, genetics, chemically induced)
• Cystic Fibrosis Transmembrane Conductance Regulator (genetics, metabolism, therapeutic use)
• Liver Diseases (drug therapy)