Population pharmacokinetics of voriconazole and initial dosage optimization in patients with talaromycosis

Abstract

The high variability and unpredictability of the plasma concentration of voriconazole (VRC) pose a major challenge for clinical administration. The aim of this study was to develop a population pharmacokinetics (PPK) model of VRC and identify the factors influencing VRC PPK in patients with talaromycosis. Medical records and VRC medication history of patients with talaromycosis who were treated with VRC as initial therapy were collected. A total of 233 blood samples from 69 patients were included in the study. A PPK model was developed using the nonlinear mixed-effects models (NONMEM). Monte Carlo simulation was applied to optimize the initial dosage regimens with a therapeutic range of 1.0–5.5 mg/L as the target plasma trough concentration. A one-compartment model with first-order absorption and elimination adequately described the data. The typical voriconazole clearance was 4.34 L/h, the volume of distribution was 97.4 L, the absorption rate constant was set at 1.1 h-1, and the bioavailability was 95.1%. Clearance was found to be significantly associated with C-reactive protein (CRP). CYP2C19 polymorphisms had no effect on voriconazole pharmacokinetic parameters. ‏Monte Carlo simulation based on CRP levels showed that a loading dose of 250 mg/12 h and a maintenance dose of 100 mg/12 h are recommended for patients with CRP ≤ 96 mg/L, whereas a loading dose of 200 mg/12 h and a maintenance dose of 75 mg/12 h are recommended for patients with CRP > 96 mg/L. The average probability of target attainment of the optimal dosage regimen in CRP ≤ 96 mg/L and CRP > 96 mg/L groups were 61.3% and 13.6% higher than with empirical medication, and the proportion of Cmin > 5.5 mg/L decreased by 28.9%. In conclusion, the VRC PPK model for talaromycosis patients shows good robustness and predictive performance, which can provide a reference for the clinical individualization of VRC. Adjusting initial dosage regimens based on CRP may promote the rational use of VRC.

Renal Replacement Therapy as a New Indicator of Voriconazole Clearance in a Population Pharmacokinetic Analysis of Critically Ill Patients

“…Our study found that an increase in qCRP was related to a decrease in voriconazole CL, which has been widely confirmed in previous studies [ 39 , 51 , 52 , 53 , 54 , 55 , 56 ]. This is attributed to the fact that, in an inflammatory state, inflammatory mediators can bind to cytokine and toll-like receptor 4 receptors on the cell membrane and regulate the expression of transporters and drug-related metabolic enzymes through the NF-κB signaling pathway [ 57 ].…”

“…This is attributed to the fact that, in an inflammatory state, inflammatory mediators can bind to cytokine and toll-like receptor 4 receptors on the cell membrane and regulate the expression of transporters and drug-related metabolic enzymes through the NF-κB signaling pathway [ 57 ]. These findings suggested that metabolizing enzymes, including cytochrome P450 (CYP) isoenzymes, are downregulated by inflammatory cytokines, resulting in a decrease in voriconazole CL [ 56 , 58 ]. Furthermore, the inflammatory status may modulate polymorphisms in PK-related genes, which may influence the metabolic pathway from voriconazole to voriconazole N-oxide [ 54 ].…”

Enhancing voriconazole therapy in liver dysfunction: exploring administration schemes and predictive factors for trough concentration and efficacy

“…We observed a robust association between C-reactive protein (CRP) and the efficacy of VRZ ( p = 0.0003), which is consistent with previous reports ( Chen et al, 2022 ; Jiang et al, 2022 ), demonstrating a significant impact of CRP on the pharmacokinetic profile of VRZ. Regrettably, only 44 CRP values were retrievable from the HIS, which were insufficient to provide a conclusive explanation for the efficacy observed in our final analysis.…”