Efficacy and safety of voriconazole and CYP2C19 polymorphism for optimised dosage regimens in patients with invasive fungal infections.

The aim of this study was to determine an optimum voriconazole target concentration, to study the influence of CYP2C19 gene status on metabolism of voriconazole and to identify a dose-adjustment strategy for voriconazole according to CYP2C19 polymorphism in patients with invasive fungal infections. A total of 328 voriconazole trough plasma concentrations (C(min)) were collected and monitored from 144 patients. Information on efficacy and safety was obtained. Voriconazole therapy was effective in 81.9% of patients (118/144), and 12.5% (18/144) exhibited signs of hepatotoxicity. The relationships between voriconazole C(min) and clinical response and hepatotoxicity were explored using logistic regression, and a target clinical C(min) range of 1.5-4 mg/L was identified. Values of voriconazole C(min) and the ratio of C(min) to concentration of voriconazole-N-oxide (C(min)/C(N)) of poor metabolisers (PMs) were significantly higher than extensive metabolisers and intermediate metabolisers. Model-based simulations showed that PM patients could be safely and effectively treated with 200 mg twice daily orally or intravenously, and non-PM patients with 300 mg twice daily orally or 200mg twice daily intravenously. This study highlighted that voriconazole C(min) and C(min)/C(N) are strongly influenced by CYP2C19 polymorphism, and gene-adjusted dosing is important to achieve therapeutic levels that maximise therapeutic response and minimise hepatotoxicity.