Population pharmacokinetics, safety and dosing optimization of
voriconazole in patients with liver dysfunction: a prospective study
Abstract
Aims This study aimed to explore the relationship between voriconazole
trough concentration (Ctrough) and toxicity, identify the factors
significantly associated with voriconazole pharmacokinetic parameters
and propose an optimised dosing regimen for patients with liver
dysfunction. Methods The study prospectively enrolled 51 patients with
272 voriconazole concentrations. Receiver operating characteristic (ROC)
curves were used to explore the relationship between voriconazole
Ctrough and toxicity. The pharmacokinetic data was analysed with
nonlinear mixed-effects method. Dosing simulations stratified by TBIL
(TBIL-1: TBIL < 51 μmol/L; TBIL-2: 51 μmol/L ≤ TBIL
< 171 μmol/L; TBIL-3: TBIL ≥ 171 μmol/L) were performed.
Results ROC curve analysis revealed that voriconazole Ctrough of ≤ 5.1
mg/L were associated with significantly lower the incidence of adverse
events. A one-compartment pharmacokinetic model with first-order
absorption and elimination was used to describe the data. Population
pharmacokinetic parameters of clearance (CL), the volume of distribution
(V) and oral bioavailability (F) were 0.88 L/h, 148.8 L and 88.4%,
respectively. Voriconazole CL was significantly associated with total
bilirubin (TBIL) and platelet count. The V increased with weight.
Patients with TBIL-1 could be treated with loading dose of 400 mg every
12 hours (q12h) for first day and maintenance dose of 100 mg q12h
intravenously or orally. TBIL-2 and TBIL-3 patients could be treated
with loading dose of 200 mg q12h and maintenance doses of 50 mg q12h or
100 mg once daily (qd) and 50 mg qd orally or intravenously,
respectively. Conclusions TBIL-based dosing regimens provide a practical
strategy for voriconazole maximizing treatment outcomes.