Discussion

This study prospectively investigated 51 patients with liver dysfunction to develop a PPK model. The results of this analysis show that a one-compartment pharmacokinetic model with first-order absorption and elimination was able to describe voriconazole pharmacokinetics in patients with liver dysfunction.
The estimated values of the pharmacokinetic parameters CL, V, and F of voriconazole in patients with liver dysfunction (0.88 L/h, 148.8 L and 88.4%, respectively) are similar to our previous findings [17] (0.56 L/h, 134 L and 80.8%, respectively). We confirmed that voriconazole shows a significant decrease in CL in patients with liver dysfunction compared with patients without liver disease and healthy subjects (CL: 4.76-25.2 L/h) [10, 13, 25, 26]. The V is not significantly different in the presence of liver disease. Covariate model showed that TBIL and PLT are significantly associated with voriconazole CL, while WT has a significant effect on V. The inclusion of TBIL, PLT and WT reduced the inter-individual variation of CL and V (the inter-individual variation of CL decreased from 68.3% to 18.0%, and the inter-individual variation of V decreased from 15.3% to 12.0%), indicating that these covariates are important factors affecting the large variation of pharmacokinetic parameters.
TBIL was showed to be an important covariate affecting the CL of voriconazole in this study, the inclusion of TBIL resulted in a significant reduction of the OFV (ΔOFV=71.36) in the forward inclusion model-building step. The final model demonstrated that high TBIL values were significantly correlated with decreased CL. Voriconazole is mainly metabolized by the CYP450 enzyme in the liver (98%) and then excreted through the kidney and bile, with less than 2% of a dose of voriconazole is excreted into the urine as unchanged voriconazole [27]. In liver disease, a reduction in absolute liver cell mass or a decreased in metabolic enzyme activity may lead to impaired drug metabolism [16], which causes a large amount of voriconazole to accumulate in the body. Therefore, voriconazole CL is significant decrease for patients with liver dysfunction. The PLT was found to be significantly associated with CL in the present study, similar to our previous studies [17]. The reduction of PLT counts is very common in patients with cirrhosis and is correlated with severity of liver function. WT has a significant effect on V, and is positively correlated with V.
Age, CYP2C19 genotype, and PPI were not found to affect significantly the pharmacokinetic parameters of voriconazole, which is consistent with our previous analysis17. A prospective study of voriconazole by Wang et al. [28] has shown that age has a significant effect on voriconazole CL, the median voriconazole plasma concentrations in elderly (age ≥65 years) have been 80%-90% higher than those in younger patients. Another prospective study of lung transplant recipients [29] found a correlation between age and initial voriconazole Ctrough, the older patients (age ≥ 60 years) is more likely to have a higher initial Ctrough. In older patients, the activity of liver microsomal enzyme is decreased, resulting in lower CL. However, this study did not find age to have a significant effect on the pharmacokinetic parameters of voriconazole, suggesting that age has no significant effect on liver microsomal enzymes in patients with liver dysfunction. Many studies [30-33] in patients without liver disease have showed that PM patients have higher voriconazole plasma concentration compared with EM and IM patients. However, CYP2C19 polymorphisms and PPI (CYP2C19 enzyme inhibitors) seem to have no effect on the pharmacokinetic parameters of voriconazole in this study. Ohnishi et al. [34] have reported that in 31 patients with chronic liver disease (9 with chronic hepatitis, 22 with cirrhosis comprising 20 Child-Pugh type A, 1 type B, 1 type C), patients with PM polymorphisms have higher omeprazole hydroxylation indexes (a metabolite of CYP2C19 enzyme) than those with EM and IM polymorphisms, but only two Child-Pugh B and C patients were included. In patients with moderate to severe liver dysfunction, whether gene polymorphism is still an important factor affecting CYP2C19 enzyme activity is worthy of further investigation.
At present, the product information for voriconazole suggests that the standard loading dose should be used but the maintenance dosing should be halved in patients with mild-to-moderate liver disease (Child–Pugh Class A and B), however no dose recommendations in severe liver dysfunction patients are provided. It has been reported in a retrospective study [35] that oral voriconazole maintenance doses in patients with Child–Pugh class C should be reduced to approximately one-third that of patients with normal liver function, while another clinical study for acute-on-chronic liver failure (ACLF) patients [4] has proposed that voriconazole concentration can be maintained a reasonable range (1-5 mg/L) with a loading dose of 200 mg twice daily and a maintenance dose of 100 mg once daily of voriconazole dosing regimen. However, both of these studies are retrospective analyses with small sample sizes (6 cases of cirrhosis C grade and 20 cases of chronic acute liver failure, respectively), so the voriconazole dosing regimen for patients with liver dysfunction still needs further verification.
In the current study, TBIL-based simulations after intravenous and oral voriconazole were performed using voriconazole Ctrough(0.5-5.0 mg/L) as a target with the combination of MCS to optimize voriconazole dosing regimen. The results show that there is no significant difference in the PTA after voriconazole intravenous and oral administration. The dosing regimen for patients with normal liver function (loading dose: 400 mg q12h; maintenance dose: 200 mg q12h) is probably inappropriate for patients with liver dysfunction, and is associated with a high risk of toxicity (51.6%-97.8% probability of toxicity). Patients with TBIL-1 could be treated with loading dose of 400 mg q12h for 2 doses followed by maintenance dose of 100 mg q12h intravenously or orally which is the dosing regimen of patients with mild-to-moderate liver disease (Child–Pugh Class A and B) in the medication label of voriconazole, but it’s not suitable for patients with TBIL-2 and TBIL-3. For patients with TBIL-2 and TBIL-3, the PTA of voriconazole within 30 days is greater than 90% when TBIL-2 and TBIL-3 patients could be treated with maintenance doses of 50 mg q12h or 100mg qd and 50 mg qd orally or intravenous, respectively. Meanwhile, the steady-state time (about 30 days) of voriconazole is markedly prolonged in patients with liver dysfunction, a loading dose of 200 mg q12h orally or intravenously must be given to rapidly achieve the voriconazole target concentration.
This study found that adverse events have generally occurred at higher voriconazole concentrations, and ROC curve analysis revealed a significant association between voriconazole Ctrough and toxicity, with voriconazole Ctrough of ≤ 5.1 mg/L found to minimize the incidence of adverse events, similar to the studies by Dolton et al [36]. and Troke et al [37].
There are several limitations to the present study. Firstly, this study has a small sample size and it is a single-center study. Secondly, this study did not find the CYP2C19 genotype to have a significant effect on the pharmacokinetic parameters of voriconazole, possibly due to the small number of patients with PM and UM polymorphisms included. Thus, the results need further validation in future clinical studies.