Results
Patients’ characteristics
51 patients with a total of 272 voriconazole plasma concentrations were
included in this study. The demographics and clinical information of the
patients is summarized in Table 1 . Patients with Child-Pugh
grade C or MELD score greater than 15 scored made up more than 70% of
all patients. There was a significant variation in the voriconazole
plasma concentrations, with an average concentration of 3.9 mg/L and a
range of 0.06-14.08 mg/L. There were 190 plasma Ctrough,
and 82 plasma concentrations collected within the 24 hours after
intravenous or oral administration. There were four types of CYP2C19
genotypes in the present study, 1 UM patients (CYP2C19*17*17), 24 EM
patients (CYP2C19*1*1), 21 IM patients (CYP2C19*1*2, CYP2C19*1*3), and 5
PM patients (CYP2C19*2*2, CYP2C19*2*3). The genotypes were divided into
three groups (UM/EM, IM and PM) for the purposes of PPK model
development.
Voriconazole concentrations and adverse
events
Adverse events were reported in 20 patients (39.2%) during voriconazole
therapy. These included dizziness, hallucinations and visual disturbance
such as altered colour discrimination, blurred vision and photophobia.
The median duration from voriconazole initiation to onset of adverse
events was 2 days (range, 1 to 12 days). The median voriconazole
concentration at the time of these adverse events was significantly
higher than in patients without adverse events (6.5 mg/L versus 2.3
mg/L, P <0.0001). A ROC curve analysis confirmed
voriconazole Ctrough to be a significant predictor of
adverse events, with a voriconazole Ctrough of ≤ 5.1
mg/L found to minimize the incidence of adverse events (Figure 1).
Population Pharmacokinetic
Analysis
A one-compartment pharmacokinetic model with first-order oral absorption
and elimination adequately describe the data. Inter-individual
variability of the parameters was best fitted to an exponential
equation, and residual error was best characterized by a proportional
error model.
The analysis identified the PLT and TBIL as the most significant
covariates for CL and WT as a significant covariate for V.
The typical value of CL, V and F of
voriconazole obtained in the final model are 0.88 L/h, 148.8 L and
88.4%, respectively. The terminal
elimination half-life (t1/2) was 117.2 h, and the time
for voriconazole to reach steady state is about 30 days. The
inter-individual variability of CL and V in final model were 18.0% and
12.0%, respectively. Compared to the base model (CL: 68.3%, V:
15.3%), the inter-individual variability of CL and V significantly
decreased in the final model. The η of F is fixed as 0 due to the large
of shrinkage for F. The final model parameters and the result of
bootstrap are summarized in Table 2.
Goodness-of-fit plots from the basic and final models presenting the
correlations between population-predicted concentrations and
individual-predicted versus observed concentrations of voriconazole are
showed in Figure 2. The figure shows improvement in the final
model fit has been improved compared to the base model. There was no
structural bias in the plot of population-predicted and
individual-predicted concentrations versus observed concentrations. The
conditional weighted residuals (CWRES) of population‐predicted
concentrations and time for voriconazole are showed in Figure
3. The CWRES random distribution was around zero for
voriconazole. The distribution was
symmetrical distribution and no
concentration- or time-related trends were observed for voriconazole.
Most of points were within an acceptable range (-2 to 2).
The bootstrap (n=1000) procedure is summarized in Table 2. All 1000
bootstrap runs fit successfully. The parameter estimates of the final
model are similar to those of the bootstrap, suggested good robustness
and stability of the final model. The parameters of the final model are
within the 95% confidence interval (CI) obtained from bootstrap
replications, indicating that the estimates for the pharmacokinetic
parameters in the final model are accurate and that the model is stable.
Monte Carlo simulation
The elimination of voriconazole is markedly prolonged (typical value of
CL: 0.88 L/h) in patients with liver dysfunction, which means it reaches
the steady state about 30 days
later. Furthermore, fungal infection treatment usually takes one month
or more. Therefore, the dosing regimens were simulated at 30-days for
treatment. Simulations of oral or intravenous administration did not
demonstrated a significant difference. The probability of
Ctrough target attainment after intravenous and oral
administration for 30 days of standard unadjusted dosing regimen of
voriconazole for patients without liver dysfunction (Loading dose: 400
mg q12h, maintenance dose: 200 mg q12h) are showed in Table 3. The
maximum PTA of all group is less than 50%. Apart from TBIL-1 patients,
there was 90% overexposure in the other groups. The results for the
recommended dosing regimen of voriconazole for patients with
mild to moderate liver dysfunction
(Child-Pugh A and B) (Loading dose: 400 mg q12h, maintenance dose: 100
mg q12h) are showed in Table 4. The
PTA for patients with TBIL-1 is 91.7% and 85.2%, administered orally
and intravenously respectively. It indicated that dosing regimen with a
loading dose of 400 mg q12h for 2 doses, followed by a maintenance dose
of 100 mg q12h administered
intravenously or orally for patients
with TBIL-1 is suitable.
For patients with TBIL-2 and TBIL-3, we simulated the achievement of
Ctrough after oral
and intravenous administration with different loading doses (400 mg, 300
mg and 200 mg q12h) in order to determine the loading dose, which are
showed in Table 5. An oral and intravenous loading dose of 200 mg q12h
demonstrated the highest PTA (>90%). Utilizing this loading dose,
different maintenance doses and dosing intervals were simulated to
determine the optimal maintenance dose. The PTA of the examined
maintenance doses are showed in Table 6. The simulations demonstrated
that a maintenance dose of 50 mg q12h or 100 mg qd orally or
intravenously for TBIL-2 patients, and a maintenance dose of 50 mg qd
orally or intravenously for TBIL-3 patients were optimal. The
simulated 30 days median
voriconazole Ctrough versus time
profiles based on the optimal
intravenous or oral dosing regimen are showed in Figure 4. The results
showed that the median voriconazole Ctrough in all
patients were within the target concentration range (0.5-5.0 mg/L), and
the distribution of Ctrough was centralized between 2
and 4 mg/L.