Pharmacokinetic and Pharmacodynamic Properties of Oral Voriconazole in Patients with Invasive Fungal Infections

STUDY OBJECTIVES To assess the pharmacokinetic and pharmacodynamic (PK/PD) properties of voriconazole and to investigate the relationship between PK/PD parameters and the efficacy of a fixed-dose oral regimen in the treatment of invasive fungal infections (IFIs). DESIGN Prospective and observational PK/PD study. SETTING A university-affiliated medical center. PATIENTS Fifteen hospitalized patients with proven IFIs who were treated with oral voriconazole for at least 2 weeks. METHODS We investigated the PK/PD properties of voriconazole using a noncompartmental analysis in 15 patients. RESULTS Marked interpatient variation in voriconazole pharmacokinetic properties was noted including peak plasma concentrations (median 2.31 mg/L, range 1.06-4.01 mg/L), 12-hour area under the plasma concentration-time curve (AUC(tau)) (median 21.18 hr mg/L, range 7.71-42.07 hr mg/L), ratio of the unbound drug AUC over 24 hours (fAUC(24)) divided by the minimum inhibitory concentration (fAUC(24): MIC; median 62.61, range 6.48-415.30), and the free trough plasma concentration (C-min) divided by the MIC (fC(min): MIC; median 1.81, range 0.46-15.52). There was a good correlation between voriconazole C-min and AUC(tau) (R-2=0.805). Voriconazole therapy was effective in 66.7% of patients (10/15). No significant difference was observed with regard to successful clinical response between the patients with a fAUC(24): MIC and fC(min): MIC values higher than 25 and higher than 1 (10/12 vs 10/13, respectively; chi(2)=1.61, p=0.688). CONCLUSION There is substantial interpatient variability in the PK/PD properties of voriconazole. fAUC(24):MIC values higher than 25 and fC(min): MIC values higher than 1 may predict clinical response in patients with IFIs. Designing an optimal dosage regimen based on individual PK/PD properties will improve the efficacy in patients with IFIs.