Challenging recommended oral and intravenous voriconazole doses for improved efficacy and safety: population pharmacokinetics-based analysis of adult patients with invasive fungal infections.
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2012
- doi: 10.1093/cid/cis437
- issn: 1058-4838
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T. Buclin et al., « Challenging recommended oral and intravenous voriconazole doses for improved efficacy and safety: population pharmacokinetics-based analysis of adult patients with invasive fungal infections. », Serveur académique Lausannois, ID : 10.1093/cid/cis437
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BACKGROUND: Recommended oral voriconazole (VRC) doses are lower than intravenous doses. Because plasma concentrations impact efficacy and safety of therapy, optimizing individual drug exposure may improve these outcomes. METHODS: A population pharmacokinetic analysis (NONMEM) was performed on 505 plasma concentration measurements involving 55 patients with invasive mycoses who received recommended VRC doses. RESULTS: A 1-compartment model with first-order absorption and elimination best fitted the data. VRC clearance was 5.2 L/h, the volume of distribution was 92 L, the absorption rate constant was 1.1 hour(-1), and oral bioavailability was 0.63. Severe cholestasis decreased VRC elimination by 52%. A large interpatient variability was observed on clearance (coefficient of variation [CV], 40%) and bioavailability (CV 84%), and an interoccasion variability was observed on bioavailability (CV, 93%). Lack of response to therapy occurred in 12 of 55 patients (22%), and grade 3 neurotoxicity occurred in 5 of 55 patients (9%). A logistic multivariate regression analysis revealed an independent association between VRC trough concentrations and probability of response or neurotoxicity by identifying a therapeutic range of 1.5 mg/L (>85% probability of response) to 4.5 mg/L (
