Effect of concomitant rifampin and clarithromycin on elexacaftor-tezacaftor-ivacaftor using a physiologically based pharmacokinetic (PBPK) modeling approach

Background: Rifampin (RIF) is a first-line therapy for Mycobacterium avium complex (MAC) in people with cystic fibrosis (CF); but it induces CYP3A, leading to significant drug–drug interactions (DDIs) with elexacaftor/tezacaftor/ivacaftor (ETI). Clarithromycin (CLR), a strong CYP3A inhibitor, may counteract rifamycin–mediated induction, potentially enabling co-administration with ETI. Research design and methods: DDIs between RIF, CLR, and ETI were evaluated using physiologically based pharmacokinetic (PBPK) modeling. Two-drug (e.g., RIF–CLR, RIF–ivacaftor, CLR–ivacaftor) and three-drug combinations (e.g., RIF–CLR–midazolam) were validated against published data. The models were then used to predict interactions between RIF, CLR, and ETI. Results: Predicted AUC_0–24h ratios for ETI with RIF and CLR administration were 0.29 (95% CI 0.26–0.32), 0.30 (95% CI 0.26–0.35), and 0.19 (95% CI 0.16–0.23) for elexacaftor, tezacaftor, and ivacaftor, respectively. Steady-state concentrations exceeded the EC₅₀ targets in 99%, 94%, and 43% of the simulated population, respectively. Lower RIF or higher CLR doses modestly improved ivacaftor target attainment. Conclusions: Concomitant RIF and CLR reduced ETI plasma exposures. Elexacaftor and tezacaftor concentrations remained above EC₅₀ targets, while ivacaftor was slightly below. Variability in CLR pharmacokinetics during RIF co-administration may contribute to interindividual differences in ETI exposure.