A literature search of the following databases was performed from the date of inception to December 2008 to identify relevant articles: MEDLINE (from 1950), EMBASE (from 1980), BIOSIS Previews (from 1969), International Pharmaceutical Abstracts (from 1970), Web of Science (from 1965), and Cochrane Central Register of Controlled Trials. The search was limited to English-language studies involving humans and used the following search terms: “voriconazole”, “antifungals”, “therapeutic drug monitoring”, “drug levels”, “drug monitoring”, “invasive fungal infections”, “invasive candidiasis”, and “aspergillosis”. Bibliographies of the relevant articles were also searched by hand to identify additional relevant literature.
The first question to be answered in determining the utility of TDM for voriconazole is whether the patient is taking the best drug for his or her specific subpopulation (disease state) and specific indication.
Voriconazole has been approved in North America for use in adults and in Europe for use in children. Current IDSA guidelines recommend voriconazole as a first-line agent for the treatment of invasive aspergillosis and as step-down oral therapy for certain cases of candidiasis. It is also indicated for the treatment of invasive fungal infections caused by Scedosporium spp. and Fusarium spp. The following discussion focuses on the major trials that have studied the use of voriconazole in invasive fungal infection, the majority of which enrolled immunocompromised patients.
The most important trial demonstrating the efficacy of voriconazole as primary treatment for invasive aspergillosis was amulticentre, randomized, nonblinded, non-inferiority trial published in 2002, which enrolled 277 immunocompromised patients with proven or probable invasive aspergillosis.39 The patients were randomly assigned to receive either voriconazole (6 mg/kg IV q12h for 2 doses, then 4 mg/kg IV q12h for a minimum of 7 days, followed by 200 mg PO bid) or amphotericin B (1-1.5 mg/kg IV daily). In a modified intention-to-treat analysis, the survival rates at 12 weeks were 71% in the voriconazole group and 58% in the amphotericin B group (hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.40-0.88; p = 0.02). Fewer adverse events were observed in the voriconazole group, with the exception of visual disturbances (which had rates of 44.8% for the voriconazole group and 4.3% for the amphotericin B group,p < 0.001).
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Similar results were obtained in an open, nonblinded, noncomparative trial published in the same year. In that trial, 48% of the patients receiving voriconazole met the primary efficacy end point of a good response (defined as complete or partial response, as determined by clinical and radiographic change). Almost half of the patients received voriconazole as salvage therapy, whereas the remainder received it as primary treatment. The incidence of visual disturbance was 11%, lower than the 44.8% in the study by Herbrecht and others. A similar trial performed later involved 36 patients with subacute invasive and chronic pulmonary aspergillosis who were receiving voriconazole as primary or salvage therapy. The rates of therapeutic response and toxic effects were comparable to those observed by Denning and others. Smaller observational studies and case reports have also demonstrated the efficacy of voriconazole for treatment of invasive aspergillosis in specific populations of immunocompromised patients.
The only literature to date that has investigated the role of voriconazole for treatment of invasive aspergillosis in patients without immunocompromise was a retrospective trial involving patients with chronic necrotizing pulmonary aspergillosis. In that study, 58% of the patients had a response to voriconazole by the end of follow-up, after a median duration of treatment of 9 months.