Physiologically Based Pharmacokinetic Model for Voriconazole and Prediction of its Interactions with Midazolam and Alfentanil

Authors: Macwan J, Lukacova V, Fraczkiewicz G
Conference: AAPS
Keywords: alfentanil, drug-drug interactions (DDIs), fungal infections, mechanistic absorption, midazolam, PBPK modeling, voriconazole
Software: GastroPlus®
Division: PBPK

Purpose

Voriconazole (formerly known as UK-109,496), is a second-generation triazole antifungal agent widely used in the treatment of invasive fungal infections. Voriconazole is a potent competitive (reversible) and time-dependent inhibitor of CYP3A4, which metabolizes ~50% of the marketed drugs. Coadministration of CYP3A4 substrates with voriconazole is highly likely to result in clinically relevant drug-drug interactions (DDIs). The primary route for voriconazole elimination is metabolism, mainly catalyzed by the isoenzyme CYP2C19 with minor contributions of other enzymes. Therefore, pharmacokinetics (PK) and the extent of DDIs is influenced by the CYP2C19 genotype.

By Joyce S. Macwan, Viera Lukacova, Grazyna Fraczkiewicz

2019 AAPS Annual Meeting PharmSci 360, November 3-6, 2019, San Antonio, Texas