Role of Therapeutic Drug Monitoring of Voriconazole in the Treatment of Invasive Fungal Infections

Abstract

Background: Voriconazole is a broad-spectrum, second-generation triazole antifungal agent with demonstrated efficacy in the treatment of invasive fungal infections caused by Aspergillus spp. and Candida spp. Given the characteristically poor prognosis of patients with invasive fungal infections and the protracted duration of treatment required, therapeutic monitoring of voriconazole is, in theory, an attractive method to optimize antifungal therapy. Objective:To determine the utility of therapeutic drug monitoring for voriconazole. Methods:A previously published decision-making algorithm was used to assess the currently available literature on therapeutic drug monitoring of voriconazole.Results: Several analytical methods can be used to quantify plasma or serum concentrations of voriconazole. Reasons for therapeutic monitoring of this drug include wide variability both within and between individuals secondary to drug properties, drug-drug interactions, and disease states. Furthermore, voriconazole follows nonlinear pharmacokinetics with saturable hepatic clearance. Another potential factor in favour of therapeutic drug monitoring for voriconazole is genetic polymorphism of CYP2C19, whereby patients who are homozygous for poor metabolism (about 19% of non-Indian Asians) can have 4-fold greater exposure to voriconazole. The concentrations of this drug are also greater in patients with hepatic impairment. Drug-drug interactions with other substrates of CYP2C9, CYP2C19, and CYP3A4 can also alter voriconazole concentrations. However, the correlations between plasma concentrations of voriconazole and its efficacy and toxicity are not well defined. Although lower and upper target thresholds of 0.25-2 mg/L and 4-6 mg/L, respectively, have been suggested, studies to date have not been appropriately designed or powered to reveal any definitive association. Conclusions:Routine therapeutic drug monitoring of voriconazole is not recommended except in certain circumstances, such as lack of response to therapy or evidence of toxicity, in which case selective monitoring of voriconazole concentrations may be of clinical utility. Méthodes : Un algorithme de prise de décision publié a été utilisé pour évaluer la documentation actuellement disponible sur le suivi thérapeutique pharmacologique du voriconazole. Résultats :Plusieurs méthodes analytiques peuvent servir à quantifier les concentrations sériques ou plasmatiques de voriconazole. Les raisons de recourir au suivi thérapeutique pharmacologique de ce médicament sont notamment la grande variabilité intra et interindividuelle attribuable aux propriétés du médicament, aux interactions médicament-médicament et aux affections. De plus, le voriconazole a un comportement pharmacocinétique non linéaire en raison d'une clairance hépatique saturable. Un autre facteur potentiellement en faveur du suivi thérapeutique pharmacologique du voriconazole est le polymorphisme génétique du CYP2C19 qui, chez les patients homozygotes ayant un faible métabolisme (environ 19 % des Asiatiques ...

Therapeutic Drug Monitoring of Voriconazole in the Management of Invasive Fungal Infections: A Critical Review

“…This variability is a result of several factors, including the nonlinear pharmacokinetic properties of voriconazole, genetic polymorphisms in the CYP2C19 gene which encodes for the CYP2C19 enzyme, drug-drug interactions, age, hepatic dysfunction, and other factors [11,14,15]. Due to the morbidity and mortality associated with IFIs and the large variability described above, it is speculated that therapeutic drug monitoring (TDM) may be beneficial for optimizing both efficacy and safety.…”

“…In fact, TDM is supported and recommended by both the US FDA and the Infectious Diseases Society of America (IDSA) [10,13,15]. In particular, evidence for TDM was established for special populations, such as those not responding to standard doses or those demonstrating toxicity [14].…”

Role of Therapeutic Drug Monitoring in Pulmonary Infections: Use and Potential for Expanded Use of Dried Blood Spot Samples

“…The efficacy of these drugs is mostly monitored by the 403 viral load of the patient. There are no important drug-drug interactions influencing the plasma 404 concentration of these drugs [62,64,66]. TDM is not recommended for most of these drugs [64].…”

“…In general, the antiviral drugs are excreted renally, therefore dose adjustment is recommended in 402 patients with impaired renal function [61][62][63][64][65]. The efficacy of these drugs is mostly monitored by the 403 viral load of the patient.…”

Hospital resource use of patients receiving isavuconazole vs voriconazole for invasive mold infections in the phase III SECURE trial

“…However, this agent exhibits non-linear pharmacokinetics 12 , is associated with multiple drug-drug interactions 12 , and has a potential for renal toxicity owing to the use of a cyclodextrin-based vehicle in its intravenous formulation 13 . There is also controversy over the need for therapeutic drug monitoring with this agent in high-risk patients 12,14 . Isavuconazonium sulfate is a novel, broadspectrum, cyclodextrin-free triazole antifungal prodrug, which was approved in 2015 by the US Food and Drug Administration for the primary treatment of invasive aspergillosis and mucormycosis 15 .…”