Abstract
Aims
Voriconazole is a broad-spectrum antifungal agent for the treatment of
invasive fungal infections. There is limited information about the
pharmacokinetics and appropriate dosage of voriconazole in patients with
liver dysfunction. This study aimed to explore the relationship between
voriconazole trough concentration and toxicity,
identify the factors significantly
associated with voriconazole pharmacokinetic parameters and
propose an optimised voriconazole
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 trough concentration
(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 body weight. Patients with TBIL-1
could be treated with a loading dose of 400 mg every 12 hours (q12h) for
first day, followed by a maintenance dose of 100 mg q12h administered
intravenously or orally. TBIL-2 and TBIL-3 patients could be treated
with a 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
Lower doses and longer administration intervals should be considered for
patients with liver dysfunction. TBIL-based dosing regimens provide a
practical strategy for achieving voriconazole therapeutic targets and
therefore maximizing treatment outcomes.
Keywords: voriconazole; population pharmacokinetics; dosing
regimen; liver dysfunction; therapeutic drug monitoring.
This clinical study was registered in Chinese Clinical Trial Registry
(http://www. chictr.org.cn; Registration number: ChiCTR-RRC-1800015015).