Pharmacokinetic variability of CFTR modulators from standard and alternative regimens

Abstract

Elexacaftor, tezacaftor, ivacaftor (ETI) is a CFTR modulator combination approved for use in ∼90 % of people with cystic fibrosis (pwCF) over 2 years old. While most pwCF tolerate this therapy well, some are intolerant to standard dosing, and others show little response. Clinical providers may adjust ETI dosing to combat these issues, but these adjustments are not well guided by pharmacokinetic evidence. Our post-approval study aimed to describe pharmacokinetic variability of ETI plasma concentrations in 15 participants who were administered a standard or reduced dose. ETI were quantified by LC-MS/MS in plasma samples taken prior to the morning dose. Results showed non-significant differences for each compound regardless of dosing regimen and after dose equivalence normalization. The majority of participants in both dosing groups had concentrations expected to elicit clinical response to ETI therapy. These findings indicate that dose reduction may be a viable strategy to maintain clinical benefit while managing intolerance.

Keywords: Cystic fibrosis; Elexacaftor; Ivacaftor; LC-MS/MS; Pharmacokinetics; Tezacaftor.

Fig. 1.

Modulator dosing and concentrations. A) Standard (STD) compared to reduced (RED) daily dose equivalents (DDE). Dotted line indicates standard dose. B) 0h plasma concentrations for all three ETI compounds for STD versus RED. Triangle symbol represents those who reported non-response to therapy, while circles represent those reporting side effects. Dotted lines at 5488 ng/mL, 2050 ng/mL, and 750 ng/mL for ELX, TEZ, and IVA, respectively, indicate previously established comparable concentrations for patients that are primarily responders to ETI therapy [17]. C) 0h plasma concentrations were normalized to the daily dose equivalent. All comparisons used an unpaired t-test, two-tailed. Log-transformed data were also analyzed with similar results.