Voriconazole

Author: C. Cordonnier

Author address:

Henri Mondor University Hospital, and University Paris-Est
Créteil, France

Full conference title:

8th Trends in Medical Mycology, Organised under the auspices of EORTC-IDG and ECMM, 6-9 October 2017, Belgrade, Serbia

Date: 16 October 2017

Abstract:

Voriconazole is historically the first antifungal triazole which has been shown to dramatically improve the outcome of invasive aspergillosis. Voriconazole has a broad in vitro spectrum against yeasts and moulds, including Aspergillus spp., Candida spp., Fusarium spp., Scedosporium apiospermum, dematiaceous moulds, Cryptococcus neoformans, and dimorphic fungi. It shares with other triazoles to inhibit cytochrome P450 3A4 – and subsequent drug–drug interactions with commonly administered concomitant medications -and a variable bioavailability, especially in fragile patients. It is additionally a substrate of CYP 3A4. Routine therapeutic drug monitoring is recommended both for improving efficacy and limiting side effects, and both in adults and children with similar efficacy ( > 1-2 mg/L) and safety (<5-6 mg/l) trough targets. When compared to other antifungals, voriconazole has intermediate plasma protein binding, lipophilicity and volume of distribution. Its concentrations in lung tissue are comparable to plasma and has been shown to be 11 times the one of plasma in epithelial lining cells recovered by broncho-alveolar lavage in lung transplant recipients. Voriconazole has also an excellent penetration in the brain and is the drug of choice for cerebral aspergillosis. Voriconazole is indicated for the first-line treatment of invasive aspergillosis, for candidemia in non-neutropenic patients, and serious infections caused by Scedosporium and Fusarium spp. Furthermore, in Europe the agent is licensed for fluconazole-resistant serious invasive Candida infections and in the USA for esophageal candidiasis and disseminated Candida infections in skin, abdomen, kidney, bladder wall, and wounds. The most frequent possible serious adverse events are prolonged visual disturbances, QT interval prolongation, and hepatic toxicity and mainly occur in severely ill patients and/or those with relevant underlying conditions. Fifteen years ago, in a large randomized trial, voriconazole has been shown to have significantly higher response and survival rates than deoxycholate ampho-B in the first line treatment of invasive aspergillosis. Since that time, none antifungal has been shown to have a superior efficacy than voriconazole in invasive aspergillosis and voriconazole remains the standard of care for first line treatment in this indication, both in American and European guidelines. A more recent trial with combination of voriconazole plus anidulafungin did not show significant benefit of the combination over voriconazole alone in invasive aspergillosis. Voriconazole has also been assessed for primary prophylaxis of invasive fungal disease (IFD) in two large prospective studies in allogeneic stem cell transplant recipients. The drug was given from transplant until three months after transplant, eventually longer in case of graft-versushost disease. It was compared to fluconazole in the first trial and to itraconazole in the second one. The incidence of invasive fungal disease in these two trials was low, especially in the second study, and most of the patients were at standard risk. Although none of these studies showed a significant benefit on the incidence of IFD or on survival, there was a significant reduction of IFD in the more at-risk subgroup of acute myeloid leukemia patients in the first study. Although the drug was given for a median of 96 days, no major safety issue was observed. Voriconazole is also widely used for secondary prophylaxis in patients with previous IFD on the basis of an open study and is a major drug for treatment of fusariosis. It should be noticed that the voriconazole studies have been essential for improving the design of antifungal trials, to better overcome the difficulties of such trials in complex patient populations, and to define primary and secondary endpoints in this setting. In that way, the development of voriconazole has provided major achievements in clinical mycology. 

Abstract Number: S19.3

Conference Year: 2017

Link Conference abstract: 

TIMM 8th (2017)

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