Mechanism of Action
Voriconazole is an azole antifungal drug. The primary mode of action of voriconazole is the inhibition of fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell wall and may be responsible for the antifungal activity of voriconazole.
A potential for development of resistance to voriconazole is well known. The mechanisms of resistance may include mutations in the gene ERG11 (encodes for the target enzyme, lanosterol 14-α-demethylase), upregulation of genes encoding the ATP-binding cassette efflux transporters i.e., Candida drug resistance (CDR) pumps and reduced access of the drug to the target, or some combination of those mechanisms. The frequency of drug resistance development for the various fungi for which this drug is indicated is not known.
Fungal isolates exhibiting reduced susceptibility to fluconazole or itraconazole may also show reduced susceptibility to voriconazole, suggesting cross-resistance can occur among these azoles. The relevance of cross-resistance and clinical outcome has not been fully characterized. Clinical cases where azole cross-resistance is demonstrated may require alternative antifungal therapy.
Voriconazole has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections.
Candida glabrata (In clinical studies, the voriconazole MIC90 was 4 µg/mL)1
Fusarium spp. including Fusarium solani
The following data are available, but their clinical significance is unknown. At least 90 percent of the following fungi exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for voriconazole against isolates of similar genus or organism group.
However, the effectiveness of voriconazole in treating clinical infections due to these fungi has not been established in adequate and well-controlled clinical trials:
Candida lusitaniae Candida guilliermondii
- In clinical studies, voriconazole MIC90 for C. glabrata baseline isolates was 4 µg/mL; 13/50 (26%) C. glabrata baseline isolates were resistant (MIC ≥4 µg/mL) to voriconazole. However, based on 1054 isolates tested in surveillance studies the MIC90 was 1 µg/mL.
For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.
CYP2C19, significantly involved in the metabolism of voriconazole, exhibits genetic polymorphism. Approximately 15–20% of Asian populations may be expected to be poor metabolizers. For Caucasians and Blacks, the prevalence of poor metabolizers is 3–5%. Studies conducted in Caucasian and Japanese healthy subjects have shown that poor metabolizers have, on average, 4-fold higher voriconazole exposure (AUCτ ) than their homozygous extensive metabolizer counterparts. Subjects who are heterozygous extensive metabolizers have, on average, 2-fold higher voriconazole exposure than their homozygous extensive metabolizer counterparts [see Clinical Pharmacology (12.3)].
Two-year carcinogenicity studies were conducted in rats and mice. Rats were given oral doses of 6, 18 or 50 mg/kg voriconazole, or 0.2, 0.6, or 1.6 times the RMD on a body surface area basis. Hepatocellular adenomas were detected in females at 50 mg/kg and hepatocellular carcinomas were found in males at 6 and 50 mg/kg. Mice were given oral doses of 10, 30 or 100 mg/kg voriconazole, or 0.1, 0.4, or 1.4 times the RMD on a body surface area basis. In mice, hepatocellular adenomas were detected in males and females and hepatocellular carcinomas were detected in males at 1.4 times the RMD of voriconazole.
Voriconazole demonstrated clastogenic activity (mostly chromosome breaks) in human lymphocyte cultures in vitro. Voriconazole was not genotoxic in the Ames assay, CHO HGPRT assay, the mouse micronucleus assay or the in vivo DNA repair test (Unscheduled DNA Synthesis assay).
Voriconazole administration induced no impairment of male or female fertility in rats dosed at 50 mg/kg, or 1.6 times the RMD.
Voriconazole, administered orally or parenterally, has been evaluated as primary or salvage therapy in 520 patients aged 12 years and older with infections caused by Aspergillus spp., Fusarium spp., and Scedosporium spp.
Voriconazole was studied in patients for primary therapy of IA (randomized, controlled study 307/602), for primary and salvage therapy of aspergillosis (non-comparative study 304) and for treatment of patients with IA who were refractory to, or intolerant of, other antifungal therapy (non-comparative study 309/604).
Study 307/602 – Primary Therapy of Invasive Aspergillosis
The efficacy of voriconazole compared to amphotericin B in the primary treatment of acute IA was demonstrated in 277 patients treated for 12 weeks in a randomized, controlled study (Study 307/602). The majority of study patients had underlying hematologic malignancies, including bone marrow transplantation. The study also included patients with solid organ transplantation, solid tumors, and AIDS. The patients were mainly treated for definite or probable IA of the lungs. Other aspergillosis infections included disseminated disease, CNS infections and sinus infections. Diagnosis of definite or probable IA was made according to criteria modified from those established by the National Institute of Allergy and Infectious Diseases Mycoses Study Group/European Organisation for Research and Treatment of Cancer (NIAID MSG/EORTC).
Voriconazole was administered intravenously with a loading dose of 6 mg/kg every 12 hours for the first 24 hours followed by a maintenance dose of 4 mg/kg every 12 hours for a minimum of 7 days. Therapy could then be switched to the oral formulation at a dose of 200 mg every 12 hours. Median duration of IV voriconazole therapy was 10 days (range 2–85 days). After IV voriconazole therapy, the median duration of PO voriconazole therapy was 76 days (range 2–232 days).
Patients in the comparator group received conventional amphotericin B as a slow infusion at a daily dose of 1.0–1.5 mg/kg/day. Median duration of IV amphotericin therapy was 12 days (range 1–85 days). Treatment was then continued with OLAT, including itraconazole and lipid amphotericin B formulations. Although initial therapy with conventional amphotericin B was to be continued for at least two weeks, actual duration of therapy was at the discretion of the investigator. Patients who discontinued initial randomized therapy due to toxicity or lack of efficacy were eligible to continue in the study with OLAT treatment.
A satisfactory global response at 12 weeks (complete or partial resolution of all attributable symptoms, signs, radiographic/bronchoscopic abnormalities present at baseline) was seen in 53% of voriconazole treated patients compared to 32% of amphotericin B treated patients (Table 15). A benefit of voriconazole compared to amphotericin B on patient survival at Day 84 was seen with a 71% survival rate on voriconazole compared to 58% on amphotericin B (Table 13).
Table 13 also summarizes the response (success) based on mycological confirmation and species.
|Voriconazole||Ampho B *||Stratified Difference(95% CI) †|
|n/N (%)||n/N (%)|
|Efficacy as Primary Therapy|
|Satisfactory Global Response ‡||76/144 (53)||42/133 (32)||21.8%(10.5%, 33.0%)p<0.0001|
|Survival at Day 84 §||102/144 (71)||77/133 (58)||13.1%(2.1%, 24.2%)|
|Success by Species|
|Success n/N (%)|
|Overall success||76/144 (53)||42/133 (32)|
|Mycologically confirmed ¶||37/84 (44)||16/67 (24)|
|A. fumigatus||28/63 (44)||12/47 (26)|
Study 304 – Primary and Salvage Therapy of Aspergillosis
In this non-comparative study, an overall success rate of 52% (26/50) was seen in patients treated with voriconazole for primary therapy. Success was seen in 17/29 (59%) with Aspergillus fumigatus infections and 3/6 (50%) patients with infections due to non-fumigatus species [A. flavus (1/1); A. nidulans (0/2); A. niger (2/2); A. terreus (0/1)]. Success in patients who received voriconazole as salvage therapy is presented in Table 14.
Study 309/604 – Treatment of Patients with Invasive Aspergillosis who were Refractory to, or Intolerant of, other Antifungal Therapy
Additional data regarding response rates in patients who were refractory to, or intolerant of, other antifungal agents are also provided in Table 16. In this non-comparative study, overall mycological eradication for culture-documented infections due to fumigatus and non-fumigatus species of Aspergillus was 36/82 (44%) and 12/30 (40%), respectively, in voriconazole treated patients. Patients had various underlying diseases and species other than A. fumigatus contributed to mixed infections in some cases.
For patients who were infected with a single pathogen and were refractory to, or intolerant of, other antifungal agents, the satisfactory response rates for voriconazole in studies 304 and 309/604 are presented in Table 14.
|A. fumigatus||43/97 (44%)|
Nineteen patients had more than one species of Aspergillus isolated. Success was seen in 4/17 (24%) of these patients.
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