A pharmacokinetic/pharmacodynamic analysis of a standard voriconazole regimen in different CYP2C19 genotypes by Monte Carlo simulation.

The objective of this study was to evaluate the standard voriconazole dosage regimen (maintenance dose was 200 mg bid orally) against Aspergillus infections in different CYP2C19 genotypes from a pharmacokinetic/pharmacodynamic (PK/PD) perspective.Monte Carlo simulation (MCS) was applied to simulate 5,000 patients by integrating published pharmacokinetic (PK) parameters, variability of PK parameters on CYP2C19 genotypes and microbiological data.The standard dosage regimen for poor metabolizers (PM) with Aspergillus infections was effective except A. versicolor, for heterozygous extensive metabolizers (HEM), Aspergillus fumigatus, A. terreus and A. nidulans infections could be treated effectively with the standard dosage regimen; for extensive metabolizers (EM), the standard voriconazole dosage regimen failed to achieve the best outcome for the six Aspergillus spp. Increasing dose (e.g. 300 mg bid) or even changing the antifungal drug was needed for EM and most HEM patients with Aspergillus infection.Instead of using a standard dosage regimen for all patients, the voriconazole dosage regimen needs to be optimized for patients with different CYP2C19 genotypes.