Virtual Hepatic and Plasma Exposures of Voriconazole Administered to Cytochrome P450 2C19 Poor Metabolizers Predicted by Simplified and Full Pharmacokinetic Modeling Systems: Possible Causal Factor for Hepatic Disorders Seen in a Japanese Database

The broad-spectrum antifungal agent voriconazole elicits different responses. Polymorphisms in cytochrome P450 (P450) 2C19 may partially explain this variability. This study generated virtual plasma/hepatic exposures to voriconazole in Japanese P450 2C19 poor metabolizers using both simplified and population-based full physiologically based pharmacokinetic (PBPK) modeling systems. The input parameters for the simplified PBPK model were based on the reported plasma concentrations for a 200-mg dose of voriconazole; the predicted concentrations in extensive metabolizers were in good accordance with the reported data. For poor metabolizers, the in vivo hepatic intrinsic clearance was reduced to 14.5 from 39.1 L/h; the plasma concentrations for poor metabolizers generated by the simplified PBPK model were consistent with reported values. The virtual maximum plasma/hepatic concentrations of voriconazole and the areas under the concentration-time curves in extensive and poor metabolizers were generated using the simplified and full PBPK models; the results of the two models were in good agreement. High hepatic exposure to voriconazole was predicted in poor metabolizers. This finding could be related to liver disorders, e.g., to adverse events seen in the Japanese Adverse Drug Event Report database. These results suggest that virtual plasma/hepatic exposures to voriconazole in P450 2C19 poor metabolizers can be evaluated using either simplified or full PBPK modeling systems. A half-dose of voriconazole is recommended in many countries worldwide for P450 2C19 poor metabolizer patients; despite the limited references to P450 2C19 polymorphisms in current Japanese drug labeling, the in silico information provided here could be clinically informative.