Impact of voriconazole plasma concentrations on treatment response in critically ill patients

Abstract

Summary What is known and objective Several authors have demonstrated the relationship between voriconazole concentrations and the risk of therapeutic failure and adverse events However, the information about voriconazole concentrations in the critically ill patient is scarce. The aim of this study was to analyse the plasma concentrations and pharmacokinetic behaviour of voriconazole in critically ill patients and their association with the treatment response and development of toxicity. Methods A prospective, observational study was conducted. Patients admitted to an intensive care unit and on treatment with intravenous voriconazole were included. Plasma concentrations were measured between days 4 and 7 from the start of the treatment. The pharmacokinetic analysis was performed using the NONMEM® software. A regression model was used to evaluate the variables associated with the values outside the therapeutic range, as well as the relationship between the plasma concentrations and the treatment response and the development of hepatotoxicity. Results and discussion A total of 33 patients were included. Plasma concentrations outside the therapeutic range (1‐5.5 mg/L) were observed in 15 patients, being above the established range in 9 (27.3%) cases, and below it in 6 (18.2%) cases. The presence of a bilirubin value of >1.5 mg/dL and a C‐reactive protein >100 mg/dL was associated with supra‐therapeutic concentrations. Voriconazole concentrations greater than 5.5 mg/dL were associated with the development of hepatotoxicity. What is new and conclusions There is a wide variation in voriconazole concentrations in critically ill patients, being associated with a high frequency of adverse events. Close monitoring of these values is required in order to decrease the risk of therapeutic failure and toxicity.

A Large Retrospective Assessment of Voriconazole Exposure in Patients Treated with Extracorporeal Membrane Oxygenation

“…In our study, presenting the largest patient cohort simultaneously treated with voriconazole and ECMO, the extensive intra- and interpatient variability in voriconazole exposure was confirmed [ 1 , 16 , 24 , 27 ]. Therapeutic drug monitoring (TDM) is recommended and performed in clinical practice but despite drug monitoring, we still found 48% subtherapeutic samples, which is a lot, certainly in this severely ill population.…”

“…This is a high proportion but corresponds to the proportions described in two previous published studies in critically ill patients (48% and 53%) [ 24 , 25 ]. In contrast, several other studies reported lower rates of subtherapeutic voriconazole concentrations, around 20%, although in some studies in a population only partially admitted at the ICU [ 26 , 27 , 28 , 29 ]. In all the above-mentioned studies, voriconazole trough concentrations were considered subtherapeutic if lower than 1.0 or 1.5 mg/L, while we defined a lower limit of > 2 mg/L.…”

“…Most guidelines recommend a lower target of 1-2 mg/L, with higher targets (>2 mg/L) for severe infections, treatment of fungi with an elevated MIC value or diseases with a poor prognosis, which may be appropriate in a critically ill population [30,31]. Moreover, a large variability was also observed in the previously published studies, with a reported %CV by Ruiz et al of 77.7% [24,27].…”

Voriconazole therapeutic drug monitoring in critically ill patients improves efficacy and safety of antifungal therapy

“…29 Ruiz et al conducted a prospective study with 33 critically ill patients, and the VPC outside the optimum range (1.0-5.5 mg/L) was observed in 15 patients (45.5%), and VPC greater than 5.5 mg/L was closely related to the development of hepatotoxicity. 30 Myrianthefs et al conducted a small sample prospective study with 18 ICU patients and found that the VPC of 53% (16/30) of the critically ill patients was less than 1 mg/L, and after administering a loading dose of 6 mg/kg followed by a maintenance dose of 3-4 mg/kg, no adverse events occurred in the study. 31 These results indicated that there was a high variation in VPC in critically ill patients, and the correlations between VPC and adverse events were not obvious.…”

“…Yi et al performed a retrospective study with 122 patients (47% of the patients were critically ill) to investigate the distribution of VPC, and the results showed that 61% of the patients reached the optimum range (1‐5.5 mg/L), and non‐therapeutic VPC was strongly related to adverse events requiring discontinuation 29 . Ruiz et al conducted a prospective study with 33 critically ill patients, and the VPC outside the optimum range (1.0‐5.5 mg/L) was observed in 15 patients (45.5%), and VPC greater than 5.5 mg/L was closely related to the development of hepatotoxicity 30 . Myrianthefs et al conducted a small sample prospective study with 18 ICU patients and found that the VPC of 53% (16/30) of the critically ill patients was less than 1 mg/L, and after administering a loading dose of 6 mg/kg followed by a maintenance dose of 3‐4 mg/kg, no adverse events occurred in the study 31 .…”