Pharmacokinetics of Voriconazole in Peritoneal Fluid of Critically Ill Patients.

Data on the distribution of voriconazole (VRC) in the human peritoneal cavity are sparse. This prospective study aimed to describe the pharmacokinetics of intravenous VRC in the peritoneal fluid of critically ill patients. A total of 19 patients were included. Individual pharmacokinetic curves, drawn after single (first dose on day 1) and multiple (steady-state) doses, displayed a slower rise and lower fluctuation of VRC concentrations in peritoneal fluid than in plasma. Good but variable penetration of VRC into the peritoneal cavity was observed, and the median (range) peritoneal fluid/plasma ratios of the area under the concentration-time curve (AUC) were 0.54 (0.34 to 0.73) and 0.67 (0.63 to 0.94) for single and multiple doses, respectively. Approximately 81% (13/16) of the VRC steady-state trough concentrations (Cmin,ss) in plasma were within the therapeutic range (1 to 5.5 µg/mL), and the corresponding Cmin,ss (median [range]) in peritoneal fluid was 2.12 (1.39 to 3.72) µg/mL. Based on the recent 3-year (2019 to 2021) surveillance of the antifungal susceptibilities for Candida species isolated from peritoneal fluid in our center, the aforementioned 13 Cmin,ss in peritoneal fluid exceeded the MIC90 of C. albicans, C. glabrata, and C. parapsilosis (0.06, 1.00, and 0.25 µg/mL, respectively), which supported VRC as a reasonable choice for initial empirical therapies against intraabdominal candidiasis caused by these three Candida species, prior to the receipt of susceptibility testing results.

Population pharmacokinetics and limited sampling strategies of polymyxin B in critically ill patients.

OBJECTIVES: To characterize the pharmacokinetics (PK) of polymyxin B in Chinese critically ill patients. The factors significantly affecting PK parameters are identified, and a limited sampling strategy for therapeutic drug monitoring of polymyxin B is explored. METHODS: Thirty patients (212 samples) were included in a population PK analysis. A limited sampling strategy was developed using Bayesian estimation, multiple linear regression and modified integral equations. Non-linear mixed-effects models were developed using Phoenix NLME software. RESULTS: A two-compartment population PK model was used to describe polymyxin B PK. Population estimates of the volumes of central compartment distribution (V) and peripheral compartment distribution (V2), central compartment clearance (CL) and intercompartmental clearance (Q) were 7.857 L, 12.668 L, 1.672 L/h and 7.009 L/h. Continuous renal replacement therapy (CRRT) significantly affected CL, and body weight significantly affected CL and Q. The AUC0-12h of polymyxin B in patients with CRRT was significantly lower than in patients without CRRT. CL and Q increased with increasing body weight. A limited sampling strategy was suggested using a two-sample scheme with plasma at 0.5h and 8h after the end of infusion (C0.5 and C8) for therapeutic drug monitoring in the clinic. CONCLUSIONS: A dosing regimen should be based on body weight and the application of CRRT. A two-sample strategy for therapeutic drug monitoring could facilitate individualized treatment with polymyxin B in critically ill patients.

Population pharmacokinetic model-guided optimization of intravenous voriconazole dosing regimens in critically ill patients with liver dysfunction.

STUDY OBJECTIVES: This study aimed to establish a population pharmacokinetic (PPK) model of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction and to explore the optimal dosing strategies in specific clinical scenarios for invasive fungal infections (IFIs) caused by common Aspergillus and Candida species. DESIGN: Prospective pharmacokinetics study. SETTING: The intensive care unit in a tertiary-care medical center. PATIENTS: A total of 297 plasma VRC concentrations from 26 critically ill patients with liver dysfunction were included in the PPK analysis. METHODS: Model-based simulations with therapeutic range of 2-6 mg/L as the plasma trough concentration (Cmin ) target and the free area under the concentration-time curve from 0 to 24 h (ƒAUC24 ) divided by the minimum inhibitory concentration (MIC) (ie, ƒAUC24 /MIC) ≥25 as the effective target were performed to optimize VRC dosing regimens for Child-Pugh class A and B (CP-A/B) and Child-Pugh class C (CP-C) patients. RESULTS: A two-compartment model with first-order elimination adequately described the data. Significant covariates in the final model were body weight on both central and peripheral distribution volume and Child-Pugh class on clearance. Intravenous VRC loading dose of 5 mg/kg every 12 h (q12h) for the first day was adequate for CP-A/B and CP-C patients to attain the Cmin target at 24 h. The maintenance dose regimens of 100 mg q12h or 200 mg q24h for CP-A/B patients and 50 mg q12h or 100 mg q24h for CP-C patients could obtain the probability of effective target attainment of >90% at an MIC ≤0.5 mg/L and achieve the cumulative fraction of response of >90% against C. albicans, C. parapsilosis, C. glabrata, C. krusei, A. fumigatus, and A. flavus. Additionally, the daily VRC doses could be increased by 50 mg for CP-A/B and CP-C patients at an MIC of 1 mg/L, with plasma Cmin monitored closely to avoid serious adverse events. It is recommended that an appropriate alternative antifungal agent or a combination therapy could be adopted when an MIC ≥2 mg/L is reported, or when the infection is caused by C. tropicalis but the MIC value is not available. CONCLUSIONS: For critically ill patients with liver dysfunction, the loading dose of intravenous VRC should be reduced to 5 mg/kg q12h. Additionally, based on the types of fungal pathogens and their susceptibility to VRC, the adjusted maintenance dose regimens with lower doses or longer dosing intervals should be considered for CP-A/B and CP-C patients.

Voriconazole pharmacokinetics in a critically ill patient during extracorporeal membrane oxygenation.

The pharmacokinetics (PK) of several drugs including antimicrobials might be highly altered during extracorporeal membrane oxygenation (ECMO) therapy. We present the change of voriconazole (VRC) PK during ECMO in a critically ill patient who received intravenous VRC at a maintenance dose of 200 mg every 12 h for empirical antifungal therapy. Two PK profiles were drawn before and after the initiation of ECMO therapy. Though the trough levels (both C0 and C12) with ECMO were slightly lower than that without ECMO (12.58 and 12.84 vs. 14.02 µg/mL), the peak levels and the area under the concentration-time curve from 0 h to 6 h (AUC0-6) were comparable (16.36 vs. 16.06 µg/mL and 90.78 vs. 91.45 µg·h/mL, respectively), indicating that VRC plasma exposure during ECMO therapy did not greatly decrease in our patient. The circuit factors including the type of membrane should be taken into account to further identify the effects of ECMO on the PK of VRC.

Pharmacokinetics of intravenous voriconazole in patients with liver dysfunction: A prospective study in the intensive care unit.

OBJECTIVES: To characterize the pharmacokinetics (PK) of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction. METHODS: Patients with liver dysfunction in the intensive care unit (ICU) were included prospectively. The Child-Pugh score was used to categorize the degree of liver dysfunction. The initial intravenous VRC dosing regimen comprised a loading dose of 300 mg every 12 h for the first 24 h, followed by 200 mg every 12 h. The first PK curves (PK curve 1) were drawn within one dosing interval of the first dose for 17 patients; the second PK curves (PK curve 2) were drawn within one dosing interval after a minimum of seven doses for 12 patients. PK parameters were estimated by non-compartmental analysis. RESULTS: There were good correlations between the area under the curve (AUC0-12) of PK curve 2 and the corresponding trough concentration (C0) and peak concentration (Cmax) (r2 = 0.951 and 0.963, respectively; both p < 0.001). The median half-life (t1/2) and clearance (CL) of patients in Child-Pugh class A (n = 3), B (n = 5), and C (n = 4) of PK curve 2 were 24.4 h and 3.31 l/h, 29.1 h and 2.54 l/h, and 60.7 h and 2.04 l/h, respectively. In the different Child-Pugh classes, the CL (median) of PK curve 2 were all lower than those of PK curve 1. The apparent steady-state volume of distribution (Vss) of PK curve 1 was positively correlated with actual body weight (r2 = 0.450, p = 0.004). The median first C0 of 17 patients determined on day 5 was 5.27 (2.61) µg/ml, and 29.4% of C0 exceeded the upper limit of the therapeutic window (2-6 µg/ml). CONCLUSIONS: The CL of VRC decreased with increasing severity of liver dysfunction according to the Child-Pugh classification, along with an increased t1/2, which resulted in high plasma exposure of VRC. Adjusted dosing regimens of intravenous VRC should be established based on Child-Pugh classes for these ICU patients, and plasma concentrations should be monitored closely to avoid serious adverse events.