Abstract

Lurasidone is an atypical antipsychotic drug that metabolized by cytochrome P4503A4 (CYP3A4). Posaconazole is a triazole antifungal agent known to inhibit CYP3A4activity. Co-administration of these two drugs may therefore result in significant drug–drug interactions (DDIs) due to inhibition of lurasidone metabolism. In this study, physiologically based pharmacokinetic (PBPK) modeling was appliedtoinvestigate the potential DDI between lurasidone and posaconazole. PBPK models for both drugs were developed using the GastroPlus™ simulation platform based on published physicochemical properties, pharmacokinetic parameters, and metabolic characteristics. The lurasidone model incorporated CYP3A4-mediated metabolism, while the posaconazole model was established using reported clinical pharmacokinetic data. To evaluate the influence of inhibition parameters on DDI prediction, different CYP3A4 inhibition constants (Ki) obtained from literature sources were incorporated into the model. Simulations were conducted to reproduce the clinical dosing regimen, and predicted pharmacokinetic parameters, including maximum plasma concentration(Cmax) and area under the concentration–time curve (AUC), were compared across simulations. The PBPK simulations characterized the magnitude of the interaction between lurasidone and posaconazole. Differences in predicted DDI magnitude were observed depending on the source of inhibition parameters, highlighting the importance of parameter selection in PBPK-based DDI prediction. These results demonstrate the II utility of PBPK modeling as a tool for evaluating CYP3A4-mediated drug interactions and support its application in drug development and clinical pharmacology.

By Yi Shan