Physiologically-based pharmacokinetic modeling of the drug-drug interaction between ivacaftor and lefamulin in cystic fibrosis patients

Abstract

Lefamulin is being evaluated as a treatment for bacterial exacerbations in cystic fibrosis (CF). Ivacaftor is approved for the treatment of patients with CF. Lefamulin is a moderate CYP3A inhibitor and co-administration with ivacaftor may result in a drug-drug interaction (DDI). A CF population was built based on literature using the Simcyp Simulator. A previously developed and validated physiologically-based pharmacokinetic (PBPK) model for ivacaftor was used. A PBPK model for lefamulin was developed and verified. Predicted concentrations and pharmacokinetic (PK) parameters for both ivacaftor and lefamulin in healthy subjects and patients with CF were in reasonable agreement with observed data (within 1.4-fold, majority within 1.25-fold). The lefamulin model as a CYP3A4 perpetrator was validated using a different Ki value for oral (p.o.) and intravenous (i.v.) routes. The simulated changes in area under the curve of ivacaftor in patients with CF when co-administered with p.o. and i.v. lefamulin were weak-to-moderate. The predicted change in ivacaftor PK when co-administered with oral lefamulin was less than observed between ivacaftor and fluconazole. These results suggest a low liability for a DDI between lefamulin and ivacaftor in patients with CF.