Understanding Voriconazole Metabolism: A Middle-Out Physiologically-Based Pharmacokinetic Modelling Framework Integrating In Vitro and Clinical Insights

This comprehensive parent-metabolite PBPK model of VRC quantitatively elucidated the complex metabolism of the drug and emphasised the substantial impact of the primary metabolites on VRC PK. The comprehensive approach combining bottom-up and middle-out modelling, thereby accounting for VRC autoinhibition, metabolite-mediated inhibition, and the impact of CYP2C19 genetic polymorphisms, enhances our understanding of VRC PK. Moreover, the model can be pivotal in designing further in vitro experiments, ultimately allowing for extrapolation to paediatric populations, enhance treatment individualisation and improve clinical outcomes.