Expert opinion on drug metabolism & toxicology · 2026
Effect of concomitant rifampin and clarithromycin on elexacaftor-tezacaftor-ivacaftor using a physiologically based pharmacokinetic (PBPK) modeling approach.
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Sanders Madeline, Hong Eunjin, Jain Manya, Beringer Paul
Аннотация
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 AUC0-24h 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.
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 AUC0-24h 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.