Evaluation of the drug interaction between rifabutin and elexacaftor/tezacaftor/ivacaftor (ETI)

Abstract

Background: Rifampin is a guideline-recommended treatment for nontuberculous mycobacteria infections; however, it is a strong inducer of CYP3A metabolism and therefore is contraindicated in patients receiving elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA; ETI). Rifabutin (RFB), a moderate CYP3A inducer, is a potential therapeutic alternative to rifampin. A prospective, single-arm study was conducted in healthy volunteers to evaluate the effect of RFB on ETI pharmacokinetics (PK) (NCT04840862, 2022-05-09). Methods: Six adults received a single dose of ETI (100 mg/50 mg/75 mg). After a washout, subjects received 2 weeks of RFB 300 mg daily followed by a second single ETI dose. The data were analyzed using noncompartmental PK. Results: The maximum plasma concentration (Cmax) and area under the curve (AUC0-∞) values following ETI alone were consistent with published data. Both Cmax and AUC0-∞ values were significantly reduced with concomitant RFB as expected. The AUC0-∞ geometric mean ratios (GMR, 90% CI) with RFB vs. alone were: ELX (0.45, 0.35–0.58), TEZ (0.68, 0.56–0.82), and IVA (0.60, 0.45–0.78). Importantly, the AUC0-∞ GMR for IVA with RFB is significantly higher than published data with rifampin. While these data suggest ETI dose adjustment may be needed, population compartmental modeling using standard ETI dosing indicates plasma concentrations remain above half-maximal effective concentration (EC50) values, supporting maintained efficacy. RFB significantly altered IVA metabolite-to-parent ratios, but the reduced activity of M1-IVA suggests limited clinical significance. Conclusions: RFB alters ETI PK, but to a lesser extent than rifampin. These data indicate that a clinical trial evaluating the efficacy and safety of ETI with concomitant rifabutin treatment is warranted. © 2025 European Cystic Fibrosis Society