Renal replacement therapy as a new indicator of voriconazole clearance
in a population pharmacokinetic analysis of critically ill patients in
China
Abstract
Aims: The pharmacokinetic (PK) profiles of voriconazole in intensive
care unit (ICU) patients is quite different. We aimed to develop a
population pharmacokinetic (PopPK) model to evaluate the effects of
various biological covariates and the use of extracorporeal membrane
oxygenation (ECMO) and continuous renal replacement therapy (CRRT).
Methods: The modeling analysis of the pharmacokinetic parameters were
conducted using the nonlinear mixed-effects modeling method (NONMEM)
using a two-compartment model. Monte Carlo simulations (MCSs) were
performed to observe the probability of target attainment (PTA) when
receiving CRRT or not under different dosage regimens, different quick
C-reactive protein (qCRP), and different minimum inhibitory
concentration (MIC) ranges. Results: A total of 408 critically ill
patients with 746 voriconazole concentration–time data points were
included in this study. A two-compartment population PK model with qCRP,
CRRT, creatinine clearance rate (CLCR), platelet (PLT), and prothrombin
time (PT) as fixed effects was developed using the NONMEM. Conclusion:
The results showed that qCRP, CRRT, CLCR, PLT, and PT affected the PK
parameter clearance. The most commonly used clinical regimen of 200 mg
q12h is sufficient for the most common sensitive pathogens (MIC ≤ 0.25
mg/L) in China, regardless of whether CRRT is performed, and at what
level qCRP is. When the MIC is 0.5 mg/L, 200 mg q12h is insufficient
only when qCRP is less than 40 mg/L and CRRT is performed. When MIC ≥ 2
mg /L, a dose of 300 mg q12h cannot achieve ≥ 90% PTA, and a higher
dose needs to be explored.