Recommendations for the Design of Clinical Drug‐Drug Interaction Studies with Itraconazole using a Mechanistic PBPK Model

Regulatory agencies currently recommend itraconazole (ITZ) as a strong cytochrome P450 3A (CYP3A) inhibitor for clinical drug–drug interaction (DDI) studies. This work by an International Consortium for Innovation and Quality in Pharmaceutical Development working group (WG) is to develop and verify a mechanistic ITZ physiologically‐based pharmacokinetic model and provide recommendations for optimal DDI study design based on model simulations. To support model development and verification, in vitro and clinical PK data for ITZ and its metabolites were collected from WG member companies. The model predictions of ITZ DDIs with seven different CYP3A substrates were within the guest criteria for 92% of area under the concentration‐time curve ratios and 95% of maximum plasma concentration ratios, thus verifying the model for DDI predictions. The verified model was used to simulate various clinical DDI study scenarios considering formulation, duration of dosing, dose regimen, and food status to recommend the optimal design for maximal inhibitory effect by ITZ.