Understanding Voriconazole Metabolism: A Middle-Out Physiologically-Based Pharmacokinetic Modelling Framework...

Area of Science:

• Pharmacokinetics
• Drug Metabolism
• Computational Modeling

Background:

• Voriconazole (VRC) exhibits nonlinear pharmacokinetics (PK) due to saturable metabolism, autoinhibition, and metabolite-mediated inhibition.
• High inter- and intraindividual variability in VRC PK is linked to CYP2C19 genetic polymorphism and metabolite interactions.
• Voriconazole N-oxide (NO) and hydroxyvoriconazole (OHVRC) inhibit CYP enzymes, contributing to VRC PK variability and posing therapeutic challenges.

Purpose of the Study:

• To develop a whole-body physiologically-based pharmacokinetic (PBPK) model for VRC, NO, and OHVRC.
• To elucidate the complex metabolism of VRC and the impact of its metabolites on parent drug PK.
• To leverage in vitro and in vivo data using a middle-out approach for accurate modeling.

Main Methods:

• Developed a coupled parent-metabolite PBPK model using PK-Sim® and MoBi®.
• Assumed NO formation via CYP2C19, CYP3A4, and CYP2C9; OHVRC formation via CYP3A4.
• Implemented inhibition functions to describe VRC autoinhibition and metabolite-mediated inhibition on CYP enzymes.

Main Results:

• The PBPK model accurately predicted plasma concentration-time profiles for VRC in healthy adults across different CYP2C19 genotypes.
• 100% of predicted VRC AUC and 94% of Cmax values met the 1.25-fold acceptance criterion.
• All predicted AUC and Cmax values for NO and OHVRC met the twofold acceptance criterion.

Conclusions:

• The parent-metabolite PBPK model quantitatively elucidated VRC metabolism and the significant impact of its metabolites on VRC PK.
• The comprehensive modeling approach, accounting for autoinhibition, metabolite inhibition, and genetic polymorphisms, enhances understanding of VRC PK.
• The model can aid in designing in vitro experiments, extrapolating to pediatric populations, and improving treatment individualization for better clinical outcomes.