Role of Therapeutic Drug Monitoring



Invasive fungal infections are associated with substantial morbidity and mortality in immunocompromised patients, particularly high-risk populations, such as those undergoing solid organ and bone marrow transplantation, receiving chemotherapy, with HIV-positive status, and/or receiving long- term immunosuppressant therapy. Of concern, the incidence of invasive fungal infections has been increasing, along with an epidemiologic shift. Although Candida spp. remain the most common yeasts isolated in cases of fungal infection, there has been a general increase in candidiasis caused by non-albican Candida. Aspergillus spp. are the most common moulds recovered from immunocompromised patients with invasive fungal infections, but Fusarium spp., Scedosporium spp., Penicillium spp., and Zygomycetes are also on the rise. It has been proposed that these changes in incidence and epidemio- logic pattern have occurred largely because of increasing numbers of immunocompromised patients, along with use of antineoplastic and immunosuppressive agents, broad-spectrum antibiotics, prosthetic devices and grafts, and more aggressive surgical interventions. Invasive aspergillosis is a fungal infection with an incidence of 11% to 13% in high-risk populations, an overall case fatality rate of 58%, and a fatality rate as high as 90% among patients undergoing bone marrow transplant and those with infections involving the central nervous system. Current pharmacologic options for prophylaxis and treatment of invasive fungal infections include the polyenes, azoles, nucleoside analogues, and echinocandins.

Formerly known as UK-109,496, the drug voriconazole is a broad-spectrum, second-generation triazole antifungal agent with in vitro activity against Candida spp., Aspergillus spp., Fusarium spp., Scedosporium spp., and Cryptococcus neoformans. At the cellular level, voriconazole depletes the fungal cells of ergosterol and causes accumulation of methylated sterol intermediates via inhibition of the P450-dependent enzyme lanosterol 14a-demethylase, which leads to disruption of cell-wall synthesis and interruption of fungal cell growth. Voriconazole has been studied as a treatment option for both yeast and mould infections, including esophageal candidiasis, invasive candidiasis, and invasive aspergillosis. It also has demonstrated efficacy against the less common fungal infections such as fusariosis and scedosporiosis. In the most recent clinical practice guideline of the Infectious Diseases Society of America (IDSA), voriconazole has replaced ampho­tericin B as the first-line agent recommended for treatment of invasive aspergillosis. Viagra Super Active

Voriconazole is available in both IV and oral formulations, and its pharmacokinetic properties have been studied in both healthy volunteers and immunocompromised patients.12,13 Recommended dosing regimens for both adult and pediatric patients with invasive candidiasis (12 years of age and older and weighing more than 40 kg) include 2 loading doses of 6 mg/kg IV 12 h apart, followed by 3-4 mg/kg IV q12h or 200 mg PO twice daily. In light of the expected accelerated metabolic clearance among children 2 to 11 years of age, the European Medicines Agency recommends a maintenance dosage of 7 mg/kg twice daily in this population.18 Pharmacokinetic data from healthy persons given voriconazole demonstrate high oral bioavailability (between 90% and 96%). The time to maximum plasma concentration (Tmax) for voriconazole ranges from 1.43 to 1.81 h, with a corresponding maximum plasma concentration (Cmax) of 1.88 to 5.27 mg/L. In one study, bioavailability and Tmax were comparable in 18 patients with invasive candidiasis, but the data for those patients were less accurate than those obtained from healthy volunteers because of fewer sampling time points (i.e., 6 versus 12, respectively) over a 12-h period.

Plasma protein binding for voriconazole is estimated to be 58%, and such binding is independent of the concentration of the drug in the plasma. Voriconazole has a volume of distribution of 4.6 L/kg and is distributed extensively into the tissues, including the vitreous fluid, aqueous humor, cerebrospinal fluid, and bones. canadian pharmacy viagra

Voriconazole is highly metabolized by CYP2C19, CYP2C9, and, to a lesser extent, CYP3A4 into at least 8 different metabolites, all of which exhibit minimal antifungal activity. Less than 2% of the drug is excreted unchanged in urine; 80% of the drug’s metabolites are eliminated in urine, and the remainder is excreted through the fecal route. The terminal half-life is estimated at between 6 and 12 h.Variability in plasma concentration of voriconazole both within and between individuals is high. This characteristic can be attributed to several pharmacokinetic factors, including saturable hepatic clearance, age, genetic polymorphism of CYP2C19, drug-drug interactions, hepatic dysfunction, and variation in absorption. In view of the unpredictability of plasma concentrations, therapeutic drug monitoring (TDM) for voriconazole has been proposed as a way to ascertain clinical efficacy and minimize toxic effects. In their recent review articles, Smith and others and Hope and others addressed the topic of TDM for antifungal agents, discussing voriconazole briefly. Bruggemann and others and Howard and others also discussed the role of TDM for voriconazole specifically, the latter focusing exclusively on invasive aspergillosis. The review by Bruggemann and others was the most comprehensive to date and provided extensive interpretation of current data regarding the relation between concentrations of voriconazole and efficacy and toxic effects in patients. Although most previous authors have arrived at similar conclusions regarding the use of TDM to determine the efficacy and toxic effects of voriconazole, to the current authors’ knowledge, there has been no discussion of the most fundamental issues in evaluating TDM, including its practical applicability in a clinical environment. Thus, a systematic approach to determining the utility of TDM for voriconazole was warranted.
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The objective of this review was to assess, using a previously published 9-step decision-making algorithm (Figure 1), the currently available literature with a view to determining the utility of TDM for voriconazole.

Figure 1. Decision-making algorithm

Figure 1. Decision-making algorithm for clinical pharmacokinetic monitoring in the 21st century. Reproduced, with permission of the publisher, from Ensom et al.

Category: Drugs

Tags: antifungal, invasive fungal infection, pharmacokinetics, therapeutic drug monitoring, voriconazole

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