Effect of concomitant rifampin and clarithromycin on elexacaftor-tezacaftor-ivacaftor using a PBPK modeling approach

Background Rifampin (RIF) is first-line therapy for Mycobacterium avium complex (MAC) in people with cystic fibrosis (CF); but it induces CYP3A, causing 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 AUC0–24 h 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.