Alternative control limits for zero ideal characteristics: G.E. Meek and K.A. Dunning, (Univ of Akron, Ohio, USA)

Abstract

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 (Cmin) 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 Cmin and clinical response and hepatotoxicity were explored using logistic regression, and a target clinical Cmin range of 1.5–4 mg/L was identified. Values of voriconazole Cmin and the ratio of Cmin to concentration of voriconazole-N-oxide (Cmin/CN) 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 200 mg twice daily intravenously. This study highlighted that voriconazole Cmin and Cmin/CN are strongly influenced by CYP2C19 polymorphism, and gene-adjusted dosing is important to achieve therapeutic levels that maximise therapeutic response and minimise hepatotoxicity.