Introduction
Infections are common and represent
one of the most important reasons of progression of liver failure,
development of liver-related complications, and mortality in patients
with liver dysfunction [1]. Invasive fungal infections can be a
life-threatening complication in
patients with liver dysfunction and
are associated with a high morbidity and significant mortality
[2-5]. Furthermore, long-term use of broad-spectrum antibiotics and
glucocorticoids, invasive procedures including liver puncture, ascites
drainage, indwelling catheters and hemodialysis, and multiple
hospitalizations are also associated with an increased risk of invasive
fungal infections [6] and are common in patients with liver
dysfunction.
Voriconazole is a triazole antifungal agent that exhibits broad-spectrum
activity and is used for both the prevention and treatment of invasive
fungal infections [7]. Metabolism of voriconazole occurs in the
liver by hepatic cytochrome P450 isoenzymes, primarily CYP2C19 and to a
lesser extent CYP3A4 and CYP2C9 [8]. Multiple factors are already
known to be associated with variability in voriconazole
pharmacokinetics, including age, weight, liver function and genetic
polymorphism of the CYP2C19 enzyme [9-12]. Voriconazole exhibits
complex nonlinear pharmacokinetics and has a narrow therapeutic window
[13, 14]. Subtherapeutic concentrations have been associated with
therapeutic failure, and
supratherapeutic concentrations are correlated with an increased risk of
neurological, visual and hepatic toxicity [14, 15].
Therapeutic drug monitoring (TDM)
of voriconazole is advocated to improve
treatment outcomes and minimize
the risk of adverse events. As the liver plays a key role in the
disposition of voriconazole including absorption, distribution,
metabolism and excretion [16], liver dysfunction can change the
pharmacokinetic characteristics of voriconazole, increasing the risk of
voriconazole accumulation and subsequent adverse events.
The voriconazole product
information suggests that patients with mild-to-moderate liver
dysfunction (Child–Pugh class A and B) should receive half of the
maintenance dose after an unchanged loading dose. However, there is
limited information about the pharmacokinetics and appropriate dosing of
voriconazole in patients with
severe liver dysfunction (Child-Pugh class C). We have previously
demonstrated that the clearance of voriconazole was significantly
decreased in patients with liver dysfunction ]17] highlighting the
necessity to optimise voriconazole dosing regimens in these patients.
Population pharmacokinetic (PPK) analysis was used to evaluate the
pharmacokinetic characteristics and identify the measurable factors of
patient-related and clinical-related pharmacokinetic variabilities.
Monte Carlo simulation (MCS) is a valuable tool to determine dosing
regimens and optimize antibacterial therapies [18]. The present
study aims to: 1) develop a PPK model of voriconazole in patients with
liver dysfunction; 2) identify factors significantly associated with
voriconazole pharmacokinetic parameters; 3) explore the relationship
between voriconazole trough concentration (Ctrough) and
toxicity to identify the safety Ctrough range; 4)
evaluate potential voriconazole dosing regimens in patients with liver
dysfunction through Monte Carlo Simulation (MCS) utilizing final
pharmacokinetic model.