Pharmacokinetics of intravenous voriconazole in patients with liver dysfunction: A prospective study in the intensive care unit

Abstract

Objectives: To characterize the pharmacokinetics (PK) of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction. Methods: Patients with liver dysfunction in the intensive care unit (ICU) were included prospectively. The Child–Pugh score was used to categorize the degree of liver dysfunction. The initial intravenous VRC dosing regimen comprised a loading dose of 300 mg every 12 h for the first 24 h, followed by 200 mg every 12 h. The first PK curves (PK curve 1) were drawn within one dosing interval of the first dose for 17 patients; the second PK curves (PK curve 2) were drawn within one dosing interval after a minimum of seven doses for 12 patients. PK parameters were estimated by non-compartmental analysis. Results: There were good correlations between the area under the curve (AUC0–12) of PK curve 2 and the corresponding trough concentration (C0) and peak concentration (Cmax) (r2 = 0.951 and 0.963, respectively; both p < 0.001). The median half-life (t1/2) and clearance (CL) of patients in Child–Pugh class A (n = 3), B (n = 5), and C (n = 4) of PK curve 2 were 24.4 h and 3.31 l/h, 29.1 h and 2.54 l/h, and 60.7 h and 2.04 l/h, respectively. In the different Child–Pugh classes, the CL (median) of PK curve 2 were all lower than those of PK curve 1. The apparent steady-state volume of distribution (Vss) of PK curve 1 was positively correlated with actual body weight (r2 = 0.450, p = 0.004). The median first C0 of 17 patients determined on day 5 was 5.27 (2.61) μg/ml, and 29.4% of C0 exceeded the upper limit of the therapeutic window (2–6 μg/ml). Conclusions: The CL of VRC decreased with increasing severity of liver dysfunction according to the Child–Pugh classification, along with an increased t1/2, which resulted in high plasma exposure of VRC. Adjusted dosing regimens of intravenous VRC should be established based on Child–Pugh classes for these ICU patients, and plasma concentrations should be monitored closely to avoid serious adverse events. Keywords: Voriconazole, Liver dysfunction, Pharmacokinetics, Child–Pugh score