Voriconazole Pharmacokinetics Are Not Altered in Critically Ill Patients with Acute-on-Chronic Liver Failure and Continuous Renal Replacement Therapy: An Observational Study

Abstract

Infection and sepsis are a main cause of acute-on-chronic liver failure (ACLF). Besides bacteria, molds play a role. Voriconazole (VRC) is recommended but its pharmacokinetics (PK) may be altered by ACLF. Because ACLF patients often suffer from concomitant acute renal failure, we studied the PK of VRC in patients receiving continuous renal replacement therapy (RRT) with ACLF and compared it to PK of VRC in critically ill patients with RRT without concomitant liver failure (NLF). In this prospective cohort study, patients received weight-based VRC. Pre- and post-dialysis membrane, and dialysate samples obtained at different time points were analyzed by high-performance liquid chromatography. An integrated dialysis pharmacometric model was used to model the available PK data. The recommended, 50% lower, and 50% higher doses were analyzed by Monte-Carlo simulation (MCS) for day 1 and at steady-state with a target trough concentration (TC) of 0.5–3mg/L. Fifteen patients were included in this study. Of these, 6 patients suffered from ACLF. A two-compartment model with linear clearance described VRC PK. No difference for central (V1) or peripheral (V2) volumes of distribution or clearance could be demonstrated between the groups. V1 was 80.6L (95% confidence interval: 62.6–104) and V2 106L (65–166) with a body clearance of 4.7L/h (2.87–7.81) and RRT clearance of 1.46L/h (1.29–1.64). MCS showed TC below/within/above target of 10/74/16% on day 1 and 9/39/52% at steady-state for the recommended dose. A 50% lower dose resulted in 26/72/1% (day 1) and 17/64/19% at steady-state and 7/57/37% and 7/27/67% for a 50% higher dose. VRC pharmacokinetics are not significantly influenced by ACLF in critically ill patients who receive RRT. Maintenance dose should be adjusted in both groups. Due to the high interindividual variability, therapeutic drug monitoring seems inevitable.

Modeling and Simulation as a Tool to Assess Voriconazole Exposure in the Central Nervous System

“…When we look at treatment with an initial dose of 3 mg/kg/12 h of VRC on the first day and a maintenance dose of 2 mg/kg/12 h on each subsequent day, which represent a 50% reduction compared to standard treatment [ 8 , 32 ], we observed behavior similar to that of the standard dose. However, there is a decrease from the PTA for free CSF concentrations, from an MIC of 2 mg/L in the healthy group and an MIC of 4 mg/L in the infected group, and when we look at the exposures in the brain and plasma, they are less successful.…”

“…The equations used ( Equations (S1) and (S2) ), resulting doses ( Table S1 ) for simulations and the simulated concentration versus time profile ( Figures S2 and S3 ) are presented in the Supplementary Materials . The regimens tested in the simulations were based on those reported in the literature for treating fungal infections: recommended dose—initial dose of 6 mg/kg/12 h of VRC on the first day and maintenance dose of 4 mg/kg/12 h on each subsequent day—and a dosing regimen with a 50% reduced dose—initial dose of 3 mg/kg/12 h of VRC on the first day and maintenance dose of 2 mg/kg/12 h on each subsequent day (recommended for liver cirrhosis Child–Pugh A and B) [ 8 , 32 ]. First, we estimated the cerebrospinal fluid (CSF)-to-plasma unbound concentration ratio (K p,uu,CSF ) for rats by the simulation of 1000 individuals of the dataset randomly distributed.…”

Acute-on-chronic liver failure alters linezolid pharmacokinetics in critically ill patients with continuous hemodialysis: an observational study

“…Our study has the following limitations. The sample size included only 9 patients per groups, but this is a typical number of patients in PK studies [ 9 , 10 , 33 , 34 ]. We did not systematically evaluate thrombocytopenia or lactic acidosis as common adverse effects of linezolid because both findings are typical in the included population of critically ill patients, which prevents correct causal attribution.…”

“…RRT was performed as continuous veno-venous hemodialysis (CVVHD) or as a postdilution continuous veno-venous hemofiltration (CVVH) as described before [ 9 ]. Both methods were performed with Multifiltrate pro ® dialysis machines using an Ultraflux ® AV1000S hollow-fiber hemofilter (Fresenius Medical Care, Bad Homburg, Germany) with a membrane surface area of 1.8 m 2 .…”

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

“…Similarly, although the overall PK of voriconazole is considered to be virtually unaffected by any mode of renal replacement therapy [ 32 , 33 ], one previous study indicated that continuous veno-venous hemofiltration (CVVH) with an ultrafiltration rate of 35 mL/(kg·h) may affect voriconazole clearance [ 34 ]. Some experts doubt whether even small amounts of voriconazole can be adsorbed onto the hemofilter membrane in the same way as onto the ECMO membrane; however, no relevant research has confirmed this hypothesis [ 35 ].…”