Understanding variability with voriconazole using a population pharmacokinetic approach: implications for optimal...

Area of Science:

• Pharmacokinetics and Pharmacodynamics
• Genetics and Drug Metabolism
• Clinical Pharmacology

Background:

• Voriconazole exhibits highly variable, non-linear pharmacokinetics.
• The drug has a narrow therapeutic range, necessitating careful dosing.
• CYP2C19 genotype significantly influences voriconazole metabolism.

Purpose of the Study:

• To investigate the population pharmacokinetics of voriconazole in adults.
• To assess the impact of CYP2C19 genotype on voriconazole exposure.
• To evaluate the effect of drug-drug interactions on voriconazole pharmacokinetics.

Main Methods:

• Non-linear mixed effects modeling (NONMEM) was used.
• Data from six voriconazole studies were analyzed.
• Dosing simulations were performed to assess covariate effects and target attainment.

Main Results:

• A two-compartment model with Michaelis-Menten elimination best described voriconazole pharmacokinetics.
• CYP2C19 loss-of-function (LoF) alleles reduced voriconazole Vmax by 41.2%.
• Co-administered drugs (phenytoin, rifampicin, St John's wort, glucocorticoids) increased voriconazole elimination.
• Subtherapeutic trough concentrations were predicted in many patients without CYP2C19 LoF alleles, while supratherapeutic concentrations were predicted in patients with LoF alleles.

Conclusions:

• Current voriconazole dosing regimens lead to subtherapeutic exposure in many patients without CYP2C19 LoF alleles.
• Higher voriconazole doses may be needed for patients without CYP2C19 LoF alleles.
• Therapeutic drug monitoring is essential for ensuring safe and effective voriconazole exposure, especially considering CYP2C19 genotype and drug interactions.