Population pharmacokinetic modeling of voriconazole based on real-world data for dosing regimen optimization

Abstract

This study established a population pharmacokinetic model of voriconazole with the aim of adjusting the dosing regimen of voriconazole. This was a retrospective study in which clinical data from 3,002 patients were collected from their medical records. Based on the inclusion and exclusion criteria, this study included data from 96 patients to establish a population pharmacokinetic model. Following model evaluation, a dosing adjustment regimen for voriconazole was derived using Monte Carlo simulation and validated in a clinical setting. The study used a one-compartment model to fit the data, with a exponential model selected for inter-individual variability and a mixed model selected for residual variability. The model results showed that the CL of voriconazole was 4.2 L/h and the V was 75.9 L. CL was significantly correlated with creatinine clearance (CCr), and C-reactive protein (CRP), while V was significantly correlated with whether omeprazole was used in combination. According to Monte Carlo simulation results: If the trough concentration is <0.5 mg/L, then the maintenance dose should be increased by 95%. If the trough concentration is ≥ 0.5 mg/L and <1.0 mg/L, then the maintenance dose should be increased by 65%. If the trough concentration is > 5.5 and ≤7.5 mg/L, then the maintenance dose should be decreased by 35%. If the trough concentration is > 7.5 and ≤10.0 mg/L, then the maintenance dose should be decreased by 55%. If the trough concentration is > 10.0 mg/L, then the maintenance dose should be decreased by 75%. In the clinical validation study, a total of 67 patients met the new inclusion and exclusion criteria and were included in the validation analysis. Of these 67 patients, after up to three dose adjustments based on the recommendations of the population pharmacokinetic model, 61 patients (91.04%) achieved steady-state plasma concentrations within the target range. 67 patients participated in the clinical validation study. The results showed that among the 67 patients who followed the standard treatment regimen described in the package insert, 46.3% achieved the target concentration range. After applying the dose adjustment regimen derived from this study, the proportion of patients achieving the target concentration range increased to 91.04%.