A physiologically based pharmacokinetic model for voriconazole disposition predicts intestinal first-pass metabolism...

Area of Science:

• Pharmacology
• Drug Metabolism
• Pediatric Pharmacokinetics

Background:

• Pediatric pharmacokinetics are difficult to predict due to ontogeny affecting drug-metabolizing enzymes.
• Voriconazole, an antifungal, shows significant pharmacokinetic differences between adults and children.
• Hepatic metabolism is the primary clearance route for voriconazole.

Purpose of the Study:

• To develop a physiologically based pharmacokinetic (PBPK) model for voriconazole.
• To predict voriconazole pharmacokinetics in adult and pediatric populations.
• To investigate the mechanistic basis for pharmacokinetic differences between pediatric and adult populations.

Main Methods:

• Developed adult and pediatric PBPK models integrating voriconazole properties and in vitro hepatic metabolism data.
• Simulated 100 patients per model, based on published clinical trial designs and dosing.
• Validated models by comparing simulated pharmacokinetic parameters against published values and using visual predictive checks.

Main Results:

• Adult and pediatric intravenous PBPK models predicted voriconazole pharmacokinetics within 20% of observed values.
• The initial pediatric oral model overestimated oral bioavailability by twofold.
• Incorporating intestinal first-pass metabolism improved the pediatric oral model's accuracy, indicating its relevance in children.

Conclusions:

• The PBPK model suggests differential intestinal first-pass metabolism between pediatric and adult populations for voriconazole.
• This finding, if confirmed, represents the first documented instance of distinct first-pass metabolism in children versus adults.
• PBPK modeling provides a mechanistic explanation for observed pharmacokinetic variability in pediatric drug use.