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.