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.