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.