Elexacaftor-tezacaftor-ivacaftor pharmacokinetics with concurrent tacrolimus administration after lung transplant.

Abstract

Background: CFTR modulators in post-transplant people with cystic fibrosis (pwCF) are less frequently used due to uncertainty regarding effectiveness and interactions with immunosuppressive agents. Elexacaftor/tezacaftor/ivacaftor (ETI) is a triple combination cystic fibrosis (CF) therapeutic with benefits in multiple organ systems where complications can impact lung transplant (LTx) outcomes, including malnutrition, diabetes, and sinus disease. ETI use in LTx recipients is variable.

Methods: We conducted a pharmacokinetics (PK) study of concentrations of ETI parent compounds and the four major metabolites (M23-ELX, M1-TEZ, M1-IVA, M6-IVA) in a prospective non-randomized observational study, with all transplant participants concomitantly taking tacrolimus for LTx immunosuppression and excluded if taking any other medication with known interactions (e.g., azole antifungals) and compared to a non-transplant group of pwCF. We completed non-compartmental analysis (NCA) for both groups and compared the transplant to non-transplant PK parameters, as well as to published data from the manufacturer for non-transplant pwCF. Area under the curve (AUC), average concentrations (C_avg), minimum and maximum concentrations, clearance, and other parameters were determined.

Results: Twelve transplant and fourteen non-transplant participants with CF completed the study. There were no significant differences between the mean values for any PK parameters for the transplant and non-transplant groups and no substantial differences in frequency of concentrations outside the therapeutic ranges in the two groups.

Conclusions: Our data suggest there are not significant differences in concentrations of ELX, TEZ, IVA, or their major human metabolites in LTx recipients compared to non-transplant pwCF.