Toward the personalized and integrative management of voriconazole dosing during COVID-19-associated pulmonary aspergillosis

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. COVID-19-associated pulmonary aspergillosis (CAPA) has raised concerns about increased mortality, and a consensus has been recently prepared to define and manage this pathology. Voriconazole is currently recommended as first-line therapy for CAPA [1]. Voriconazole is a second-generation triazole antifungal agent extensively metabolized via cytochrome P450 (CYP450) isoenzyme CYP2C19 and, to a lesser extent, CYP2C9 and CYP3A4. Voriconazole exhibits highly variable nonlinear pharmacokinetics and a narrow therapeutic range. In addition, several conditions of critical-care unit patients, including impaired renal or hepatic function, continuous renal replacement therapy, or extracorporeal membrane oxygenation and altered volume of distribution, render plasma drug concentrations difficult to predict, making therapeutic drug monitoring (TDM) a potential key component in the treatment of CAPA. Furthermore, severe COVID-19 patients often receive multiple drugs, increasing the risk of drug–drug interactions [1]. There is growing evidence that the inflammatory state can also alter the metabolism and thus the pharmacokinetics of many drugs [2]. Given the seriousness of the inflammatory states that occur in COVID-19, particularly during “cytokine storms” and the introduction of corticosteroids as an early and efficient strategy, it is essential to study their clinical and biological impact. We observed unexpected variations of voriconazole plasma concentrations in COVID-19 patients hospitalized in an intensive care unit (ICU). In the case reported in Fig. 1, after introduction of voriconazole for ARDS-associated CAPA, inflammation markedly influenced the voriconazole trough concentration (VTC). Metabolite ratios (voriconazole N-oxide /voriconazole) were < 0.3 during the inflammatory period and > 1 outside the inflammatory period. In addition, the time during which C-reactive protein (CRP) decreased sharply (from 200.9 to 46.8 mg/L over four days) corresponds to the period of a sharp decrease in the VTC, suggesting a recovery of metabolic function. We propose an empirical algorithm to optimize the management of measuring VTC of CAPA patients to avoid misdosing (Fig. 2). First, monitoring of inflammation, at least by measuring CRP, is essential before initiation of voriconazole and then regularly to follow its evolution. As CRP levels above 96 mg/L have been identified as an independent risk factor for voriconazole overdose among hematological patients (Odds Ratio 27; IC 95% [6–106]), we propose to consider reducing maintenance doses of voriconazole if the CRP level exceeds this threshold [3]. Second, co-administration of other drugs must be carefully followed, first because of the impact of anti-inflammatory drugs, such as corticosteroids, on the inflammatory process, as well as because of potential drug-drug interactions. Because voriconazole is metabolized via CYP2C19, CYP2C9, and CYP3A4, it is among the drugs that are the most frequently associated Open Access

COVID-19-associated pulmonary aspergillosis (CAPA) has raised concerns about increased mortality, and a consensus has been recently prepared to define and manage this pathology. Voriconazole is currently recommended as first-line therapy for CAPA [1]. Voriconazole is a second-generation triazole antifungal agent extensively metabolized via cytochrome P450 (CYP450) isoenzyme CYP2C19 and, to a lesser extent, CYP2C9 and CYP3A4. Voriconazole exhibits highly variable nonlinear pharmacokinetics and a narrow therapeutic range. In addition, several conditions of critical-care unit patients, including impaired renal or hepatic function, continuous renal replacement therapy, or extracorporeal membrane oxygenation and altered volume of distribution, render plasma drug concentrations difficult to predict, making therapeutic drug monitoring (TDM) a potential key component in the treatment of CAPA. Furthermore, severe COVID-19 patients often receive multiple drugs, increasing the risk of drug-drug interactions [1]. There is growing evidence that the inflammatory state can also alter the metabolism and thus the pharmacokinetics of many drugs [2]. Given the seriousness of the inflammatory states that occur in COVID-19, particularly during "cytokine storms" and the introduction of corticosteroids as an early and efficient strategy, it is essential to study their clinical and biological impact. We observed unexpected variations of voriconazole plasma concentrations in COVID-19 patients hospitalized in an intensive care unit (ICU). In the case reported in Fig. 1, after introduction of voriconazole for ARDS-associated CAPA, inflammation markedly influenced the voriconazole trough concentration (VTC). Metabolite ratios (voriconazole N-oxide /voriconazole) were < 0.3 during the inflammatory period and > 1 outside the inflammatory period. In addition, the time during which C-reactive protein (CRP) decreased sharply (from 200.9 to 46.8 mg/L over four days) corresponds to the period of a sharp decrease in the VTC, suggesting a recovery of metabolic function.
We propose an empirical algorithm to optimize the management of measuring VTC of CAPA patients to avoid misdosing (Fig. 2). First, monitoring of inflammation, at least by measuring CRP, is essential before initiation of voriconazole and then regularly to follow its evolution. As CRP levels above 96 mg/L have been identified as an independent risk factor for voriconazole overdose among hematological patients (Odds Ratio 27; IC 95% [6-106]), we propose to consider reducing maintenance doses of voriconazole if the CRP level exceeds this threshold [3]. Second, co-administration of other drugs must be carefully followed, first because of the impact of anti-inflammatory drugs, such as corticosteroids, on the inflammatory process, as well as because of potential drug-drug interactions. Because voriconazole is metabolized via CYP2C19, CYP2C9, and CYP3A4, it is among the drugs that are the most frequently associated Open Access  with major drug-drug interactions in the ICU setting [1].
Dexamethasone is now widely used in COVID patients and induces CYP2C9, which could decrease the VTC [4]. In addition, proton-pump inhibitors widely used in the ICU are known to inhibit CYP2C9, CYP2C19, and CYP3A4, and can thus increase the VTC, except for pantoprazole [5]. Lastly, voriconazole TDM is essential for ICU patients, particularly COVID-19 patients, with the aim to maximize efficacy and minimize toxicity.
For these reasons, VTC should be performed more frequently while the CRP remains above 96 mg/L, but also when inflammation decreases. Further studies would be needed to assess whether changes in voriconazole protein binding occur during the inflammatory period, as shown for lopinavir [6].
Overall, these findings suggest that therapeutic management must take into account the high level of inflammation of CAPA patients. As it is based on parameters that are readily available in comparison with VTC, the empirical algorithm presented here, that must consider clinical and biological parameters of each patient, could be considered with the goal of improving patient management.