Development of a Physiologically Based Pharmacokinetic Model for Itraconazole Pharmacokinetics and Drug-Drug Interaction Prediction

Physiologically based pharmacokinetic (PBPK) modeling for itraconazole has been challenging due to highly variable in vitro d ata used for 'bottom-up' model building. Under-prediction of pharmacokinetics and drug-drug interactions (DDIs) following multiple doses of itraconazole has limited the use of PBPK model simulation to aid an itraconazole clinical DDI study design. The aim of this work is to develop an itraconazole PBPK model predominantly using a 'top-down' approach to enable a more accurate pharmacokinetic and DDI prediction.

An itraconazole PBPK model describing itraconazole and hydroxyl-itraconazole (OH-ITZ) was constructed in Simcyp(®). The key parameters that govern the pharmacokinetic profile, including non-linear clearance (i.e., maximum rate of reaction [V max] and the Michaelis-Menten constant [K m]) and volume of distribution for both itraconazole and OH-ITZ, were redefined by leveraging existing in vivo data. Model verification was performed by comparing the simulated itraconazole and OH-ITZ pharmacokinetic profiles with the observed clinical data. Finally, the model was used to simulate clinical DDIs between itraconazole and midazolam.

The developed PBPK model well-described the pharmacokinetics of itraconazole and OH-ITZ, and particularly captured their accumulation after repeated doses of itraconazole. This was verified with the observed data from 29 clinical studies where itraconazole solution or capsule was given as a single or multiple dose. The predicted DDI between itraconazole and midazolam was within 1.25-fold of the observed data for seven of ten studies and within 1.5-fold for nine of ten studies.

The improvement of the itraconazole PBPK model increased our confidence in using PBPK model simulations to optimize clinical itraconazole DDI study design.