PII-097 - PBPK MODELING OF LUNG TISSUE PREDICTS EFFICACY OF ELEXACAFTOR/TEZACAFTOR/IVACAFTOR WITH CONCOMITANT RIFABUTIN ADMINISTRATION.

E. Hong¹, S. Parsons², P. Beringer¹; ¹University of Southern California, Los Angeles, CA, USA, ²The Children's Hospital of the King's Daughters, Norfolk, VA, USA.

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) has significantly improved lung function in people with cystic fibrosis (CF); however, it is not recommended with concomitant use of strong CYP3A inducers (e.g., rifampin and rifabutin)[1]. This creates a therapeutic challenge to the treatment of non-tuberculosis mycobacteria (NTM) by precluding use of first-line antibiotics. We previously demonstrated that the estimated reduction in plasma AUC of ivacaftor is significantly less with rifabutin compared to rifampin (the AUC ratio 0.31 and 0.11, respectively)[2]. As lipophilic compounds, we hypothesize that lung tissue concentrations of ETI remain therapeutic during coadministration with rifabutin enabling the use of this combination without loss of efficacy.

Methods: We developed a full PBPK model of ETI which was implemented in Simcyp® Ver. 21. The models of ETI were validated against available PK and dose-response relationship data and applied to predict lung concentrations at the steady-state.

Results: The predicted lung concentrations of ETI upon rifabutin coadministration all exceeded reported in vitro half-maximal effective concentration (EC50) for chloride transport in human bronchial epithelial cells[3], with the lower 5th percentiles of trough concentrations 12.4-, 1.2-, and 1.9-fold higher than the EC50 for elexacaftor, tezacaftor, and ivacaftor, respectively. In contrast, the 5th percentiles of tezacaftor and ivacaftor lung concentrations were below the EC50 with rifampin coadministration. Stability of sweat chloride data from 2 patients receiving rifabutin and CFTR modulators confirm this result.

Conclusion: This study provides evidence in support of the use of rifabutin for the treatment of NTM in patients receiving ETI.

[1] TRIKAFTA [prescribing information]. Boston, MA, Vertex Pharmaceuticals Inc., 2019
[2] Hong, E., Rao, A.P., Beringer, P.M. EVALUATION OF THE DRUG-DRUG INTERACTION POTENTIAL OF RIFABUTIN AND ELEXACAFTOR/TEZACAFTOR/IVACAFTOR USING A PHYSIOLOGICALLY BASED PHARMACOKINETIC SIMULATION APPROACH. Ped. Pulmonol. Vol. 55, S244 (2020).
[3] U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Clinical Pharmacology and Biopharmaceutics review(s), Elexacaftor/Tezacaftor/Ivacaftor.