Determination of Plasma Unbound Fraction of Voriconazole in Patients Treated With a Prophylactic or a Curative Treatment

Abstract

Voriconazole (VOR) is a triazole antifungal used in the curative treatment of invasive fungal infections and the prophylactic treatment of opportunistic fungal infections in immunocompromised patients. It is a drug for which therapeutic drug monitoring (TDM) is highly recommended. To determine the best TDM marker, the pharmacologically active form of the drug, represented by the plasma unbound concentration (Cu) and fraction (fu), has been studied using a method based on ultrafiltration and ultra performance liquid chromatography. As albumin (Alb) is a likely factor inducing fluctuations in fu, the correlation between Alb levels and fu was carried out. Similarly, correlations between trough plasma concentrations [total concentration (Ct) and Cu] and both efficacy and safety markers were determined. Efficacy evaluation was based on monitoring fungal antigens and cultures, whereas safety was monitored by measuring bilirubin levels. In vitro, using blank human plasma, the mean fu was determined at 32.3% ± 5.5%, whereas in patients' plasmas treated with VOR, the median (5th-95th percentiles) of the unbound VOR fraction was 22.95% (14.95%-38.42%). A high correlation was found (rho = 0.956, P < 0.001) between Ct and Cu, though there was no correlation between serum Alb levels and fu, except for some patients with severe hypoalbuminemia (<25 g/L). Based on the efficacy/safety correlations, a therapeutic window has been defined ranging from 4.5 to 6.5 mg/L and 1.5 and 2.0 mg/L for trough Ct and Cu, respectively. For the first time, the relevance of new pharmacokinetic parameters, such as Cu and fu, has been explored and discussed, and our results support the current TDM protocol for VOR.