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PubMed2005

[Treatment of invasive fungal infections with voriconazole. Evaluation of experience with compassionate use of voriconazole in Spain].

Although voriconazole shows an advantageous microbiological and pharmacological profile with respect to amphotericin B and other antifungals, the cumulative experience with the use of voriconazole in patients intolerant to other antifungals or with refractory invasive fungal infections is still limited. We performed a retrospective analysis of the charts of 48 patients in 26 Spanish hospitals who were diagnosed with invasive fungal infections due to filamentous fungi or yeasts and had received voriconazole (between 1999 and 2002) as part of a compassionate use program for a mean of 59.2 days (range 1-748 days). The favorable response rate in patients with invasive, refractory aspergillosis who were treated exclusively with voriconazole was 8/12 (66%). This response rate increased to 10/12 (83%) when two other cases treated with a combination of voriconazole plus caspofungin were included. In patients with invasive candidiasis the response rate was 66% (6/9). A favorable response was achieved in 12/17 (70%) patients with invasive fungal infections due to other difficult to treat fungi (Scedosporium spp., Fusarium spp., Blastoschizomyces spp.). The tolerability and safety profile of voriconazole was good; only four patients required discontinuation of treatment due to side effects. Voriconazole is a well-tolerated, effective antifungal for the treatment of patients with refractory invasive fungal infections due to Aspergillus spp., Candida spp. and fungi resistant or refractory to other treatments.

Adolescent↗

PubMed2005

Successful treatment of Fusarium endophthalmitis with voriconazole and Aspergillus endophthalmitis with voriconazole plus caspofungin.

PURPOSE: To report successful treatment of exogenous Fusarium and Aspergillus endophthalmitis with new antifungal agents. DESIGN: Interventional case report. METHODS: Treatment of two cases is reviewed. RESULTS: A 64-year-old man developed post-cataract Fusarium moniliforme endophthalmitis. Infection persisted despite removal of the intraocular lens, three vitrectomies, and five intravitreal injections of amphotericin. Inflammation resolved and vision improved from 20/80 to 20/40 on 6 months of oral voriconazole. A 55-year-old man developed post-cataract intraocular inflammation. After three vitrectomies and removal of the intraocular lens, Aspergillus fumigatus endophthalmitis was diagnosed. Intravitreal amphotericin and systemic voriconazole were given, but one week later there were early signs of recurrence. Intravenous caspofungin was added and the eye improved. Caspofungin was continued for 6 weeks and voriconazole for 6 months. Vision improved from counting fingers to 20/80 at 6 months and 20/25 at 23 months. CONCLUSION: Voriconazole is a promising new therapy for Fusarium and Aspergillus endophthalmitis. Caspofungin may act synergistically with voriconazole in treating Aspergillus endophthalmitis.

Anti-Bacterial Agents↗

PubMed2005

Voriconazole-resistant disseminated Paecilomyces variotii infection in a neutropenic patient with leukaemia on voriconazole prophylaxis.

Paecilomyces variotii, an emerging hyalohyphomycetes, has been reported to be susceptible in vitro to voriconazole. We describe a case of disseminated P. variotii infection in a neutropenic child with relapsed leukaemia who was on voriconazole prophylaxis. The P. variotii isolate was resistant to voriconazole in vitro. The patient responded to liposomal amphotericin B.

Adolescent↗

PubMed2003

No clinically significant effect of erythromycin or azithromycin on the pharmacokinetics of voriconazole in healthy male volunteers.

AIMS: The antibiotic erythromycin is a potent inhibitor of cytochrome P450 CYP3A4 metabolism. As CYP isozymes, including CYP3A4, are involved in the metabolism of the new triazole voriconazole, this study investigated the effects of multiple-dose erythromycin or azithromycin on the steady-state pharmacokinetics of voriconazole in healthy male subjects. METHODS: In an open, randomized, parallel-group, single-centre study, 30 healthy male subjects aged 20-41 years received oral voriconazole 200 mg twice daily for 14 days plus either erythromycin (1 g twice daily on days 8-14), azithromycin (500 mg once daily on days 12-14) or placebo (twice daily on days 8-14). Only morning doses were administered on day 14. Plasma concentrations of voriconazole were measured up to 12 h postdose on days 7 and 14, and plasma pharmacokinetic parameters were calculated. Adverse events and standard laboratory test results were recorded before and throughout the study. RESULTS: Comparison of the voriconazole Cmax day 14/day 7 ratio for the voriconazole + erythromycin group with that of the voriconazole + placebo group yielded a ratio of 107.7%[90% confidence interval (CI) 90.6, 128.0]; for the voriconazole + azithromycin group, the ratio was 117.5% (90% CI 98.8, 139.7). Comparison of the voriconazole AUCtau day 14/day 7 ratios of the voriconazole + erythromycin and voriconazole + azithromycin groups with that of the voriconazole + placebo group showed ratios of 101.2% (90% CI 89.1, 114.8) and 107.9% (90% CI 95.1, 122.4), respectively. For voriconazole tmax, the differences between the day 14-day 7 calculations for the voriconazole + erythromycin or the voriconazole + azithromycin groups and that of the voriconazole + placebo group were - 0.2 h (90% CI - 0.8, 0.3) and - 0.1 h (90% CI - 0.7, 0.5), respectively. None of these changes was considered clinically relevant. The study drugs were well tolerated by subjects in all groups; the most common study drug-related adverse events were visual disturbances, reported in all groups, and abdominal pain, present in the voriconazole + erythromycin group. CONCLUSIONS: Coadministration of erythromycin or azithromycin does not affect the steady-state pharmacokinetics of voriconazole in a clinically relevant manner in healthy male subjects.

Adult↗

PubMed2003

Coadministration of voriconazole and phenytoin: pharmacokinetic interaction, safety, and toleration.

AIMS: Voriconazole is a new triazole antifungal agent, and is metabolized by the cytochrome P450 isoenzymes CYP2C9, CYP2C19, and, to a lesser extent, by CYP3A4. Phenytoin is an inducer of CYP3A4 activity, and a substrate and inducer of CYP2C9 and CYP2C19. The present studies investigated the pharmacokinetic interactions of voriconazole and phenytoin when coadministered. METHODS: Two placebo-controlled parallel-group studies were conducted in healthy male volunteers. Study A was an open-label study and investigated the effect of phenytoin (300 mg once daily) on the steady-state pharmacokinetics of voriconazole (200 mg and 400 mg twice daily). Study B was a double-blind randomized study to investigate the effects of voriconazole (400 mg twice daily) on the steady-state pharmacokinetics of phenytoin (300 mg once daily). Cmax and AUCtau were compared at days 7, 21, and 28 (Study A), and at days 7 and 17 (Study B). All adverse events were recorded. RESULTS: Study A: 21 subjects were evaluable (10 voriconazole + phenytoin, 11 voriconazole + placebo). For subjects receiving voriconazole (200 mg twice daily) plus phenytoin, the day 21/day 7 ratios for voriconazole Cmax and AUCtau were 60.7%[90% confidence interval (CI) 50.1, 73.6] and 35.9% (90% CI 29.7, 43.3), respectively. Adjusted for voriconazole + placebo, the ratios between the means were 50.7% (90% CI 38.8, 66.1) and 30.6% (90% CI 23.5, 39.7), respectively. When the dose of voriconazole was increased to 400 mg twice daily, the day 28/day 7 ratios for voriconazole Cmax and AUCtau were 134% (90% CI 89.2, 200) and 139% (90% CI 97.3, 199), respectively. Study B: 15 subjects were evaluable for pharmacokinetic assessments (six phenytoin + voriconazole, nine phenytoin + placebo). The ratios between the means for phenytoin + voriconazole/phenytoin + placebo on day 17 vs. day 7 were: phenytoin Cmax 167% (90% CI 144, 193) and phenytoin AUCtau 181% (90% CI 156, 210). All treatments were well tolerated: most adverse events were mild/moderate and transient. CONCLUSIONS: Repeat dose administration of phenytoin decreased the mean steady-state Cmax and AUCtau of voriconazole by approximately 50% and 70%, respectively. Increasing the dose of voriconazole from 200 mg to 400 mg b.d. compensated for this effect. Repeat dose administration of 400 mg b.d. voriconazole increased the mean steady-state Cmax and AUCtau of phenytoin by approximately 70% and 80%, respectively. It is therefore recommended that plasma phenytoin concentrations are monitored and the dose adjusted as appropriate when phenytoin is coadministered with voriconazole.

Adult↗

PubMed2003

Voriconazole.

BACKGROUND: Reports of resistance and intolerance to currently available antifungal agents are increasing. Voriconazole is a broad-spectrum azole antifungal agent structurally derived from fluconazole. It is indicated for the treatment of invasive aspergillosis and serious fungal infections caused by Scedosporium apiospermum and Fusarium species in patients who are unable to tolerate or are refractory to other antifungal therapy. OBJECTIVE: This article reviews the pharmacologic and pharmacokinetic properties and clinical usefulness of voriconazole. METHODS: Relevant information was identified through a search of MEDLINE (1966-December 2002), Iowa Drug Information Service (1966-December 2002), International Pharmaceutical Abstracts (1970-December 2002), and meeting abstracts of the Infectious Diseases Society of America (1996-2002) and the Interscience Conference on Antimicrobial Agents and Chemotherapy (1996-2002) using the terms voriconazole and UK-109,495. RESULTS: In head-to-head comparative trials, voriconazole appeared to be as efficacious as amphotericin B for the treatment of invasive aspergillosis and the empiric treatment of fungal infections in patients with febrile neutropenia. In clinical studies, it was as efficacious as fluconazole for the treatment of oropharyngeal and esophageal candidiasis. The results of in vitro susceptibility studies and case reports suggested that voriconazole may be useful against fluconazole- and/or itraconazole-resistant strains of Candida. Although voriconazole may be associated with a lower incidence of serious systemic adverse effects compared with amphotericin B (13.4% vs 24.3% in 1 pivotal clinical study; P = NS), major adverse effects associated with voriconazole include visual abnormalities ( approximately 30%), skin reactions ( approximately 20%), and elevations in hepatic enzymes (< or =20%). Voriconazole is available as oral and intravenous formulations. Pharmacokinetically, it has widespread distribution, including penetration into cerebral tissue. However, as 80% of voriconazole is hepatically eliminated, primarily via the cytochrome P450 (CYP) isozymes CYP2C19, CYP3A4, and CYP2C9, voriconazole has a high potential for drug interactions, and dose reduction is recommended in patients with mild to moderate hepatic dysfunction (Child-Pugh class A or B). Oral voriconazole may be preferred in patients with a creatinine clearance <50 mL/min due to the potential accumulation of the solubilizing excipient in the parenteral formulation of voriconazole. CONCLUSIONS: Voriconazole appears to be a useful alternative to conventional antifungal agents in cases of resistance or intolerance to initial therapy. However, dose adjustment is recommended in patients with hepatic dysfunction, as well as in those receiving medications that may interact with voriconazole via hepatic metabolism.

Animals↗

PubMed2003

No clinically significant pharmacokinetic interactions between voriconazole and indinavir in healthy volunteers.

AIMS: Voriconazole is a new triazole antifungal agent, and is metabolized by the cytochrome P450 isoenzymes CYP2C9, CYP2C19 and to a lesser extent by CYP3A4. Protease inhibitors, such as indinavir, are also metabolized by cytochrome P450 (mainly CYP3A4). As these drugs are likely to be coadministered, these studies were performed to assess the pharmacokinetic interactions, safety and toleration of these drugs when taken together. METHODS: Two randomized placebo-controlled studies were conducted in healthy male volunteers. Study A was an open parallel-group study of the effect of indinavir on the steady-state pharmacokinetics of voriconazole in 18 volunteers (nine subjects in each group). Subjects received voriconazole 200 mg twice daily (days 1-7), then voriconazole 200 mg twice daily + indinavir 800 mg or placebo three times daily (days 8-17). Study B was a double-blind, randomized, two-way crossover study of the effect of voriconazole on the steady-state pharmacokinetics of indinavir in 14 volunteers. They received indinavir 800 mg three times daily + voriconazole 200 mg or placebo twice daily for two 7-day treatment periods separated by a washout period of at least 7 days. Pharmacokinetic parameters were compared within treatment groups at days 7 and 17 in Study A and between treatment groups on day 7 of each period in Study B. All adverse events were recorded. RESULTS: Study A: Seventeen subjects were evaluable for pharmacokinetic analysis (eight voriconazole + indinavir, nine voriconazole + placebo). The day 17/day 7 ratios for Cmax and AUCtau were estimated as 102%[90% confidence interval (CI) 91, 114] and 107% (90% CI 98, 118), respectively. Study B: Fourteen subjects were evaluable for pharmacokinetic analysis in each treatment period. The ratios between the geometric means for indinavir + voriconazole vs. indinavir + placebo were: Cmax, 91% (90% CI 83, 101), AUCtau, 87% (90% CI 77, 100), and Cmin, 101% (90% CI 82, 125). Trough plasma concentrations of indinavir were above the concentration required to inhibit HIV replication (IC95) in both treatment periods. Voriconazole coadministered with indinavir was well tolerated in both studies. CONCLUSIONS: The coadministration of voriconazole and indinavir in healthy volunteers had no clinically significant effect on the pharmacokinetics of either voriconazole or indinavir.

Administration, Oral↗

PubMed1997

A new triazole, voriconazole (UK-109,496), blocks sterol biosynthesis in Candida albicans and Candida krusei.

Voriconazole (UK-109,496) is a novel triazole derivative with potent broad-spectrum activity against various fungi, including some that are inherently resistant to fluconazole, such as Candida krusei. In this study we compared the effect of subinhibitory concentrations of voriconazole and fluconazole on sterol biosynthesis of fluconazole-resistant and -susceptible Candida albicans strains, as well as C. krusei, in an effort to delineate the precise mode of action of voriconazole. Voriconazole MICs ranged from 0.003 to 4 microg/ml, while fluconazole MICs ranged from 0.25 to >64 microg/ml. To investigate the effects of voriconazole and fluconazole on candidal sterols, yeast cells were grown in the absence and presence of antifungals. In untreated C. albicans controls, ergosterol was the major sterol (accounting for 53.6% +/- 2.2% to 71.7% +/- 7.8% of the total) in C. albicans and C. krusei strains. There was no significant difference between the sterol compositions of the fluconazole-susceptible and -resistant C. albicans isolates. Voriconazole treatment led to a decrease in the total sterol content of both C. albicans strains tested. In contrast, exposure to fluconazole did not result in a significant reduction in the total sterol content of the three candidal strains tested (P > 0.5). Gas-liquid chromatographic analysis revealed profound changes in the sterol profiles of both C. albicans strains and of C. krusei in response to voriconazole. This antifungal agent exerted a similar effect on the sterol compositions of both fluconazole-susceptible and -resistant C. albicans strains. Interestingly, a complete inhibition of ergosterol synthesis and accumulation of its biosynthetic precursors were observed in both strains treated with voriconazole. In contrast, fluconazole partially inhibited ergosterol synthesis. Analysis of sterols obtained from a fluconazole-resistant C. albicans strain grown in the presence of different concentrations of voriconazole showed that this agent inhibits ergosterol synthesis in a dose-dependent manner. In C. krusei, voriconazole significantly inhibited ergosterol synthesis (over 75% inhibition). C. krusei cells treated with voriconazole accumulated the following biosynthetic intermediates: squalene, 4,14-dimethylzymosterol, and 24-methylenedihydrolanosterol. Accumulation of these methylated sterols is consistent with the premise that this agent functions by inhibiting fungal P-450-dependent 14alpha-demethylase. As expected, treating C. krusei with fluconazole minimally inhibited ergosterol synthesis. Importantly, our data indicate that voriconazole is more effective than fluconazole in blocking candidal sterol biosynthesis, consistent with the different antifungal potencies of these compounds.

Antifungal Agents↗

PubMed2006

Pharmacokinetic/pharmacodynamic profile of voriconazole.

Voriconazole is the first available second-generation triazole with potent activity against a broad spectrum of clinically significant fungal pathogens, including Aspergillus,Candida, Cryptococcus neoformans, and some less common moulds. Voriconazole is rapidly absorbed within 2 hours after oral administration and the oral bioavailability is over 90%, thus allowing switching between oral and intravenous formulations when clinically appropriate. Voriconazole shows nonlinear pharmacokinetics due to its capacity-limited elimination, and its pharmacokinetics are therefore dependent upon the administered dose. With increasing dose, voriconazole shows a superproportional increase in area under the plasma concentration-time curve (AUC). In doses used in children (age < 12 years) voriconazole pharmacokinetics appear to be linear. Steady-state plasma concentrations are reached approximately 5 days after both intravenous and oral administration; however, steady state is reached within 24 hours with voriconazole administered as an intravenous loading dose. The volume of distribution of voriconazole is 2-4.6 L/kg, suggesting extensive distribution into extracellular and intracellular compartments. Voriconazole was measured in tissue samples of brain, liver, kidney, heart, lung as well as cerebrospinal fluid. The plasma protein binding is about 60% and independent of dose or plasma concentrations. Clearance is hepatic via N-oxidation by the hepatic cytochrome P450 (CYP) isoenzymes, CYP2C19, CYP2C9 and CYP3A4. The elimination half-life of voriconazole is approximately 6 hours, and approximately 80% of the total dose is recovered in the urine, almost completely as metabolites. As with other azole drugs, the potential for drug interactions is considerable. Voriconazole shows time-dependent fungistatic activity against Candida species and time-dependent slow fungicidal activity against Aspergillus species. A short post-antifungal effect of voriconazole is evident only for Aspergillus species. The predictive pharmacokinetic/pharmacodynamic parameter for voriconazole treatment efficacy in Candida infections is the free drug AUC from 0 to 24 hour : minimum inhibitory concentration ratio.

Animals↗

PubMed2005

Management of endogenous fungal endophthalmitis with voriconazole and caspofungin.

PURPOSE: Voriconazole, a new generation triazole, has been shown to achieve therapeutic intraocular levels after oral administration. Caspofungin is the first approved agent from a new class of antifungals, the echinocandins. This series describes experience at two centers using these novel antifungals to treat endogenous fungal endophthalmitis. DESIGN: Retrospective review. METHODS: Treatment of five patients with Candida endophthalmitis are reviewed. Postmortem intraocular voriconazole concentrations on a sixth patient are presented as well. RESULTS: All patients had systemic cultures positive for Candida species. Three patients had prompt resolution of intraocular mycosis with intravenous and oral voriconazole, caspofungin, or both. The fourth patient with bilateral disease responded well to i.v. voriconazole and caspofungin but had a recurrence when discharged on oral voriconazole and i.v. caspofungin. This patient had a bowel resection with an ileostomy; therefore, absorption of oral voriconazole may have been inadequate. Bilateral amphotericin B intravitreal injection ultimately treated this patient. The fifth patient received 100 microg/0.1 ml of intravitreal voriconazole (final vitreous concentration approximately 25 microg/ml) followed by oral voriconazole and responded favorably. Our sixth patient had multisystem failure and passed away 1 week after initiating intravenous voriconazole for non-ocular candidemia. Postmortem HPLC analysis of the aqueous and vitreous revealed voriconazole concentrations of 1.52 microg/ml and 1.12 microg/ml, respectively (MIC90 of Candida albicans is 0.06 microg/ml). CONCLUSIONS: Voriconazole and caspofungin appear to be powerful weapons to add to the existing armamentarium against fungal endophthalmitis. Further studies are warranted to define precisely the role of these new agents alone or in combination with other antifungals.

Administration, Oral↗

PubMed2005

Voriconazole therapeutic drug monitoring in allogeneic hematopoietic stem cell transplant recipients.

Voriconazole, a new antifungal agent, is increasingly being used after HSCT. The hepatic cytochrome P450 isoenzyme 2C19 plays a significant role in voriconazole metabolism. As CYP2C19 exhibits significant genetic polymorphism, some patients metabolize voriconazole poorly resulting in increased plasma drug levels. The clinical significance of this is unknown, and the utility of monitoring voriconazole levels is unclear. Steady-state trough plasma voriconazole levels were obtained in 25 allogeneic HSCT recipients using an HPLC assay. Patients had drug levels checked once (n=13), twice (n=10), or > or =3 times (n=2) 5-18 days (median 10) after starting voriconazole or dose modification. The 41 voriconazole levels were 0.2-6.8 microg/ml (median 1.6); 6 (15%) were <0.5 (possibly below the in vitro MIC90 for Aspergillus spp.). Voriconazole concentrations correlated with aspartate aminotranferase (AST) (r=0.5; P=0.0009) and alkaline phosphatase (r=0.34; P=0.03), but not with creatinine, bilirubin and alanine aminotransferase (ALT). Since liver dysfunction is common after HSCT, it was not possible to determine if elevated AST and alkaline phosphatase levels were the cause or the consequence of higher voriconazole levels. We conclude that trough voriconazole levels vary considerably between patients, and suggest monitoring levels in patients receiving voriconazole for confirmed fungal infections, and in those with elevated AST or alkaline phosphatase levels.

Alkaline Phosphatase↗

PubMed2003

Histamine H2-receptor antagonists have no clinically significant effect on the steady-state pharmacokinetics of voriconazole.

AIMS: Voriconazole, a new triazole antifungal agent, is metabolized mainly by cytochrome P450s CYP2C19 and CYP2C9, and also by CYP3A4. The aim of this open-label, placebo-controlled, randomized, three-way crossover study was to determine the effects of cimetidine and ranitidine on the steady-state pharmacokinetics of voriconazole. METHODS: Twelve healthy male subjects received oral voriconazole 200 mg twice daily plus cimetidine 400 mg twice daily, voriconazole 200 mg twice daily plus ranitidine 150 mg twice daily, and voriconazole 200 mg twice daily plus placebo twice daily. Treatment periods were separated by at least 7 days. RESULTS: When cimetidine was administered with voriconazole, the maximum plasma voriconazole concentration (Cmax) and the area under the plasma concentration-time curve of voriconazole (AUCtau) was increased by 18.3%[90% confidence interval (CI) 6.0, 32.0] and 22.5% (90% CI 13.3, 32.5), respectively. Concomitant ranitidine had no significant effect on voriconazole Cmax or AUCtau. Time of Cmax (tmax) elimination half-life (t 1/2) or terminal phase rate constant (kel) for voriconazole were similar in all three treatment groups. Most adverse events were mild and transitory; two subjects were withdrawn due to adverse events. CONCLUSIONS: Coadministration of the histamine H2-receptor antagonists cimetidine or ranitidine does not affect the steady-state pharmacokinetics of voriconazole in a clinically relevant manner.

Administration, Oral↗

PubMed2005

Uptake and intracellular activity of voriconazole in human polymorphonuclear leucocytes.

OBJECTIVES: The intracellular penetration of voriconazole into human polymorphonuclear leucocytes (PMNs) and its intracellular activity against Candida spp. were evaluated. METHODS: The intracellular penetration of voriconazole into PMNs was evaluated by a radiometric assay. The effect of cell viability, environmental conditions, metabolic inhibitors and membrane stimulation was also studied. The intracellular activity was determined by incubation of PMNs containing intracellular blastospores in the presence of voriconazole for 3 h. RESULTS: The uptake of voriconazole by PMNs was rapid and not saturable. The cellular to extracellular concentration (C/E) ratio for voriconazole was 8.5+/-1.3. Voriconazole was rapidly released from loaded PMNs. The uptake of voriconazole was not affected by environmental temperature and cell viability. Neither the external pH nor the metabolic inhibitors affected the uptake of voriconazole. The ingestion of opsonized zymosan, but not of opsonized Candida spp., significantly decreased the levels of PMN-associated voriconazole. At the extracellular concentrations evaluated, voriconazole did not affect the intracellular survival of Candida. CONCLUSIONS: Voriconazole reached high intracellular concentrations within human PMNs. The uptake was rapid and not saturable but it did not affect the intracellular killing of Candida spp.

Antifungal Agents↗

PubMed2002

Safety and pharmacokinetics of oral voriconazole in patients at risk of fungal infection: a dose escalation study.

The objective of this study was to investigate the safety, tolerability, and pharmacokinetics of oral voriconazole in subjects at high risk of developingfungal infections. This was a multicenter, randomized, double-blind, double-dummy, parallel-group, dose escalation study with a fluconazole active control. Twenty-four subjects with hematological malignancies, solid tumors, or autologous bone marrow transplants were randomized to receive voriconazole 200 mg q 12 h (n = 9), voriconazole 300 mg q 12 h (n = 9), or fluconazole 400 mg OD (n = 6)for a period of 14 days. Blood samples were taken for the assessment of voriconazole pharmacokinetics in plasma on Days 1 and 14. Using a 200 mg q 12 h dosing regimen, geometric mean voriconazole peak plasma concentrations (Cmax) were 904 ng/ml on Day 1 and 2996 ng/ml on Day 14. Geometric mean voriconazole exposure, as measured by the area under the curve within a dosing interval (AUCtau), was 4044 and 20308 ng x h/ml on Days 1 and 14, respectively. On Day 1, geometric mean Cmax and AUC were 1.80- and 1.94-fold higher in subjects receiving voriconazole 300 mg q 12 h than in those receiving 200 mg q 12 h. Similarly, on Day 14, geometric mean Cmax and AUC were 1.56- and 1.80-fold greater in the high-dose group. Although the confidence intervals are large, this trend suggests nonlinearity in pharmacokinetics with respect to dose as seen in healthy volunteers. The absorption of orally administered voriconazole was relatively rapid, with t(max) achieved in 1.7 to 3.0 hours. There was a mean 5.4- and 5.0-fold accumulation of voriconazole over the 14-day study period in the 200 mg and 300 mg q 12 h dose groups, respectively. Voriconazole was generally safe and well tolerated. Mild, reversible visual disturbances were the most commonly reported adverse event but were not associated with treatment discontinuation. No patient developed a breakthrough fungal infection. It was concluded that in this group of patients at risk of fungal infection, voriconazole pharmacokinetics was consistent with that reported in healthy volunteers.

Administration, Oral↗

PubMed2004

Intravitreal voriconazole: an electroretinographic and histopathologic study.

BACKGROUND: Voriconazole, a novel triazole antifungal agent, presents potent activity against a broad spectrum of yeast and molds. OBJECTIVE: To determine whether voriconazole could be safely used as an intravitreal agent in the treatment of fungal endophthalmitis. METHODS: Retinal toxicity of voriconazole was examined in a rodent animal model. Voriconazole solutions were serially diluted and injected intravitreally into the eyes of normal adult Sprague-Dawley rats so that the final intravitreal concentrations were 5 microg/mL, 10 microg/mL, 25 microg/mL, 50 microg/mL, and 500 microg/mL (n = 3 for each concentration group). Saline was injected into the fellow eyes of all animals as controls. Three weeks after injections, electroretinograms were measured, and eyes were subsequently enucleated for histologic examination. RESULTS: In electroretinographic studies, maximum scotopic b-wave, intensity needed for half saturation, and saturated a-wave amplitude were measured. There was no statistically significant difference in these parameters recorded between control eyes and voriconazole-injected eyes in any concentration groups. Histologic examination with light microscopy did not reveal any retinal abnormality in the eyes with 5 to 25 microg/mL of intravitreal voriconazole. In the eyes with 50 microg/mL and 500 microg/mL of voriconazole, small foci of retinal necrosis were occasionally observed in the outer retina, especially in the eyes with 500 microg/mL of voriconazole. CONCLUSIONS: Our results demonstrate that intravitreal voriconazole of up to 25 microg/mL [corrected] causes no electroretinographic change or histologic abnormality in rat retinas. This indicates that voriconazole is a safe antifungal agent for intravitreal injection in rodents and may be used in the treatment of human fungal endophthalmitis following further study.

Animals↗

PubMed2006

Effect of voriconazole on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam.

OBJECTIVE: Our objective was to assess the effect of the antimycotic voriconazole on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam. METHODS: We used a randomized, crossover study design. Ten healthy male volunteers were given either no pretreatment (control phase) or voriconazole (voriconazole phase) orally, 400 mg twice daily on the first day and 200 mg twice daily on the second day. Midazolam was given, either 0.05 mg/kg intravenously or 7.5 mg orally, 1 hour after the last dose of voriconazole and during the control phase. Plasma concentrations of midazolam, alpha-hydroxymidazolam, and voriconazole were determined for 24 hours and pharmacodynamic variables measured for 12 hours. RESULTS: Voriconazole reduced the clearance of intravenous midazolam by 72% (P < .001) and increased its elimination half-life from 2.8 to 8.3 hours (P < .001). Voriconazole increased the peak concentration and the area under the plasma concentration-time curve of oral midazolam by 3.8- and 10.3-fold, respectively (P < .001). The bioavailability of oral midazolam was increased from 31% to 84% (P < .001). Voriconazole profoundly increased the psychomotor effects of oral midazolam (P < .001) but only weakly increased the effects of intravenous midazolam. CONCLUSION: When midazolam is given as small intravenous bolus doses, its effect is not increased to a clinically significant degree by voriconazole. The use of large midazolam doses increases the risk of clinically significant interactions also after its intravenous administration. The use of oral midazolam with voriconazole should be avoided, or substantially lower doses should be used.

Administration, Oral↗

PubMedDate not supplied

Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: a randomised non-inferiority trial.

BACKGROUND: Voriconazole has proven efficacy against invasive aspergillosis and oesophageal candidiasis. This multicentre, randomised, non-inferiority study compared voriconazole with a regimen of amphotericin B followed by fluconazole for the treatment of candidaemia in non-neutropenic patients. METHODS: Non-neutropenic patients with a positive blood culture for a species of candida and clinical evidence of infection were enrolled. Patients were randomly assigned, in a 2:1 ratio, either voriconazole (n=283) or amphotericin B followed by fluconazole (n=139). The primary efficacy analysis was based on clinical and mycological response 12 weeks after the end of treatment, assessed by an independent data-review committee unaware of treatment assignment. FINDINGS: Of 422 patients randomised, 370 were included in the modified intention-to-treat population. Voriconazole was non-inferior to amphotericin B/fluconazole in the primary efficacy analysis, with successful outcomes in 41% of patients in both treatment groups (95% CI for difference -10.6% to 10.6%). At the last evaluable assessment, outcome was successful in 162 (65%) patients assigned voriconazole and 87 (71%) assigned amphotericin B/fluconazole (p=0.25). Voriconazole cleared blood cultures as quickly as amphotericin B/fluconazole (median time to negative blood culture, 2.0 days). Treatment discontinuations due to all-cause adverse events were more frequent in the voriconazole group, although most discontinuations were due to non-drug-related events and there were significantly fewer serious adverse events and cases of renal toxicity than in the amphotericin B/fluconazole group. INTERPRETATION: Voriconazole was as effective as the regimen of amphotericin B followed by fluconazole in the treatment of candidaemia in non-neutropenic patients, and with fewer toxic effects. RELEVANCE TO PRACTICE: There are several options for treatment of candidaemia in non-neutropenic patients, including amphotericin B, fluconazole, voriconazole, and echinocandins. Voriconazole can be given both as initial intravenous treatment and as an oral stepdown agent.

APACHE↗

PubMed2001

In vitro antifungal activities of voriconazole and reference agents as determined by NCCLS methods: review of the literature.

Voriconazole (VfendTM) is a new triazole that currently is undergoing phase III clinical trials. This review summarizes the published data obtained by NCCLS methods on the in vitro antifungal activity of voriconazole in comparison to itraconazole, amphotericin B, fluconazole, ketoconazole and flucytosine. Voriconazole had fungistatic activity against most yeasts and yeastlike species (minimum inhibitory concentrations [MICs] < 2 microg/ml) that was similar or superior to those of fluconazole, amphotericin B, and itraconazole. Against Candida glabrata and C. krusei, voriconazole MIC ranges were 0.03 to 8 and 0.01 to > 4 microg/ml, respectively. For four of the six Aspergillus spp. evaluated, voriconazole MICs (< 0.03 to 2 microg/ml) were lower than amphotericin B (0.25 to 4 microg/ml) and similar to itraconazole MICs. Voriconazole fungistatic activity against Fusarium spp. has been variable. Against E oxysporum and F. solani, most studies showed MICs ranging from 0.25 to 8 microg/ml. Voriconazole had excellent fungistatic activity against five of the six species of dimorphic fungi evaluated (MIC90s < 1.0 microg/ml). The exception was Sporothrix schenckii (MIC90s and geometric mean MICs > or = 8 microg/ml). Only amphotericin B had good fungistatic activity against the Zygomycetes species (voriconazole MICs ranged from 2 to > 32 microg/ml). Voriconazole showed excellent in vitro activity (MICs < 0.03 to 1.0 microg/ml) against most of the 50 species of dematiaceous fungi tested, but the activity of all the agents was poor against most isolates of Scedosporium prolificans and Phaeoacremonium parasiticum (Phialophora parasitica). Voriconazole had fungicidal activity against most Aspergillus spp., B. dermatitidis, and some dematiaceous fungi. In vitro/in vivo correlations should aid in the interpretation of these results.

Amphotericin B↗