Population Pharmacokinetics of Voriconazole and C-reactive protein
guided Dosage Optimization in Chinese Patients with Talaromyces
marneffei Infection
Abstract
Objective To evaluate the population pharmacokinetics of voriconazole
(VRC) and identify the factors affecting it in Chinese patients with
Talaromyces marneffei infection. Based on the final model, the optimal
dosing regimen was further investigated in these patients. Methods
Patients with talaromycosis from two hospitals who met the inclusion
criteria were enrolled. Patients’ demographic information, VRC
medication history, concomitant medications and laboratory test
information data were recorded. A population pharmacokinetic model was
developed through from the nonlinear mixed-effects models (NONMEM).
Monte Carlo Simulation was applied to optimize the initial dosing
regimens. Results A total of 146 blood samples taken from 46 patients
with talaromycosis were included in the study. A one-compartment model
was used to characterize VRC pharmacokinetics. Population estimates of
clearance (CL) and volume of distribution (V) were 2.19 L/h and 88.4L,
respectively. VRC clearance was significantly associated with C-reactive
protein (CRP) level, which causing individual pharmacokinetics
variation. CYP2C19 polymorphisms had no effect on voriconazole
pharmacokinetic parameters. Based on the dosing simulations with CRP
level, the initial dosing regimens was recommended are as follows:
loading dose 150mg q12h 1day followed by maintenance dose 100mg q12h
intravenous for CRP< 40mg/L, and loading dose 75mg q12h
followed by maintenance dose 50mg q12h intravenous for CRP ≥ 40mg/L.
Conclusion A population pharmacokinetic model of VRC was successfully
established in patients with Talaromyces marneffei infection. CRP was
identified to significantly affect VRC plasma concentration. Optimizing
initial dosing regimens according to the CRP level may be useful to
guide VRC dosing in clinical practice.