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Pharmacology: Pharmacodynamics: Mechanism of Action: Voriconazole is a triazole antifungal agent. The primary mode of action of voriconazole is the inhibition of fungal cytochrome P450-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 membrane and may be responsible for the antifungal activity of voriconazole.
Voriconazole has been shown to be more selective for fungal cytochrome P-450 enzymes than for various mammalian cytochrome P-450 enzyme systems.
Pharmacokinetic/pharmacodynamic relationship: In 10 therapeutic studies, the median for the average and maximum plasma concentrations in individual subjects across the studies was 2,425 ng/ml (inter-quartile range 1,193 to 4,380 ng/ml) and 3,742 ng/ml (interquartile range 2,027 to 6,302 ng/ml), respectively. A positive association between mean, maximum or minimum plasma voriconazole concentration and efficacy in therapeutic studies was not found and this relationship has not been explored in prophylaxis studies.
Pharmacokinetic-pharmacodynamic analyses of clinical trial data identified positive associations between plasma voriconazole concentrations and both liver function test abnormalities and visual disturbances. Dose adjustments in prophylaxis studies have not been explored.
Clinical efficacy and safety: In vitro, voriconazole displays broad-spectrum antifungal activity with antifungal potency against Candida species (including fluconazole-resistant C. krusei and resistant strains of C. glabrata and C. albicans) and fungicidal activity against emerging fungal pathogens, including those such as Scedosporium or Fusarium which have limited susceptibility to existing antifungal agents.
Clinical efficacy defined as partial or complete response, has been demonstrated for Aspergillus spp. including A. flavus, A. fumigatus, A. terreus, A. niger, A. nidulans; Candida spp., including C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. tropicalis; and limited numbers of C. dubliniensis, C. inconspicua, and C. guilliermondii, Scedosporium spp., including S. apiospermum, S. prolificans; and Fusarium spp.
Other treated fungal infections (often with either partial or complete response) included isolated cases of Alternaria spp., Blastomyces dermatitidis, Blastoschizomyces capitatus, Cladosporium spp., Cocciodioides immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum, Exophiala spinifera, Fosecaea pedrosoi, Madurella mycetomatis, Paecilomyces lilacinus, Penicillum spp. including P. marneffei, Phialophora richardsiae, Scopulariopsis brevicaulis and Trichosporon spp. including T. beigelii infections.
In vitro against clinical isolates has been observed for Acremonium spp., Alternaria spp., Bipolaris spp., Cladophialophora spp., and Histoplasma capsulatum, with most strains being inhibited by concentrations of voriconazole in the range 0.05 to 2 μg/ml.
In vitro activity against the following pathogens has been shown, but the clinical significance is unknown: Curvularia spp. and Sporothrix spp.
Breakpoints: Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.
The species most frequently involved in causing human infections include C. albicans, C. parapsilosis, C. tropicalis, C. glabrata and C. krusei, all of which usually exhibit minimal inhibitory concentration (MICs) of less than 1 mg/l for voriconazole.
However, the in vitro activity of voriconazole against Candida species is not uniform. Specifically, for C. glabrata, the MICs of voriconazole for fluconazole-resistant isolates are proportionally higher than those of fluconazole-susceptible isolates. Therefore, every attempt should be made to identify Candida to species level. If antifungal susceptibility testing is available, the MIC results may be interpreted using breakpoint criteria established by European Committee on Antimicrobial Susceptibility Testing (EUCAST). (See Table 1.)
Click on icon to see table/diagram/imageClinical experience: Successful outcome in this section is defined as complete or partial response.
Aspergillus infections-efficacy in aspergillosis patients with poor prognosis: Voriconazole has in vitro fungicidal activity against Aspergillus spp. The efficacy and survival benefit of voriconazole versus conventional amphotericin B in the primary treatment of acute invasive aspergillosis was demonstrated in an open, randomised, multicentre study in 277 immunocompromised patients treated for 12 weeks. 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 oral voriconazole therapy, the median duration of oral voriconazole therapy was 76 days (range 2-232 days).
A satisfactory global response (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 31% of patients treated with comparator. The 84-day survival rate for voriconazole was statistically significant benefit was shown in favour of voriconazole for both time to death and time to discontinuation due to toxicity.
This study confirmed findings from an earlier, prospectively designed study where there was a positive outcome in subjects with risk factors for a poor prognosis, including graft versus host disease, and, in particular, cerebral infections (normally associated with almost 100% mortality).
The studies included cerebral, sinus, pulmonary and disseminated aspergillosis in patients with bone marrow and solid organ transplants, haematological malignancies, cancer and AIDS.
Candidaemia in non-neutropenic patients: The efficacy of voriconazole compared to the regimen of mphotericin B followed by fluconazole in the primary treatment of candidaemia was demonstrated in an open, comparative study. Three hundred and seventy non-neutropenic patients (above 12 years of age) with documented candidaemia were included in the study, of whom 248 were treated with voriconazole. Nine subjects in the voriconazole group and 5 in the amphotericin B followed by fluconazole group also had mycologically proven infection in deep tissue. Patients with renal failure were excluded from this study. The median treatment duration was 15 days in both treatment arms. In the primary analysis, successful response as assessed by a Data Review Committee (DRC) blinded to study medicinal product was defined as resolution/improvement in all clinical signs and symptoms of infection with eradication of Candida from blood and infected deep tissue sites 12 weeks after the end of therapy (EOT). Patients who did not have an assessment 12 weeks after EOT were counted as failures. In this analysis a successful response was seen in 41% of patients in both treatment arms.
In a secondary analysis, which utilised DRC assessments at the latest evaluable time point (EOT, or 2, 6, or 12 weeks after EOT) voriconazole and the regimen of amphotericin B followed by fluconazole had successful response rates of 65% and 71%, respectively.
The investigator's assessment of successful outcome at each of these time points is shown in the following table. (See Table 2.)
Click on icon to see table/diagram/imageSerious refractory Candida infections: The study comprised 55 patients with serious refractory systemic Candida infections (including candidaemia, disseminated and other invasive candidiasis) where prior antifungal treatment, particularly with fluconazole, had been ineffective. Successful response was seen in 24 patients (15 complete, 9 partial responses). In fluconazole-resistant non-albicans species, a successful outcome was seen in 3/3 C. krusei (complete responses) and 6/8 C. glabrata (5 complete, 1 partial response) reactions. The clinical efficacy data were supported by limited susceptibility data.
Scedosporium and Fusarium infections: Voriconazole was shown to be effective against the following rare fungal pathogens: Scedosporium spp.: Succesful response to voriconazole therapy was seen in 16 (6 complete, 10 partial responses) of 28 patients with S. apiospermum and in 2 (both partial responses) of 7 patients with S. prolificans infection. In addition, a successful response was seen in 1 of 3 patients with infections caused by more than one organism including Scedosporium spp.
Fusarium spp.: Seven (3 complete, 4 partial responses) of 17 patients were successfully treated with voriconazole. Of these 7 patients, 3 had eye, 1 had sinus, and 3 had disseminated infection. Four additional patients with fusariosis had an infection caused by several organisms; 2 of them had a successful outcome.
The majority of patients receiving voriconazole treatment of the above mentioned rare infections were intolerant of, or refractory to, prior antifungal therapy.
Duration of treatment: In clinical trials, 561 patients received voriconazole therapy for greater than 12 weeks, with 136 patients receiving voriconazole for over 6 months.
Paediatric population: Sixty-one paediatric patients aged 9 months up to 15 years who had definite or probable invasive fungal infections were treated with voriconazole. This population included 34 patients 2 to <12 years old and 20 patients 12-15 years of age.
Th majority (57/61) had failed previous antifungal therpies. Therapeutic studies included 5 patients aged 12-15 years, the remaining patients received voriconazole in the compassionate use programmes. Underlying diseases in these patients included haematological malignancies (27 patients) and chronic granulomatous disease (14 patients). The most commonly treated fungal infection was aspergillosis (43/61; 70%).
Pharmacokinetics: General pharmacokinetic characteristics: The pharmacokinetics of voriconazole have been characterised in healthy subjects, special populations and patients. During oral administration of 200 mg or 300 mg twice daily for 14 days in patients at risk of aspergillosis (mainly patients with malignant neoplasms of lymphatic or haematopoietic tissue), the observed pharmacokinetic characteristics of rapid and consistent absorption, accumulation and non-linear pharmacokinetics were in agreement with those observed in healthy subjects.
The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. Greater than proportional increase in exposure is observed with increasing dose. It is estimated that, on average, increasing the oral dose from 200 mg twice daily to 300 mg twice daily leads to a 2.5-fold increase in exposure (AUCτ). The oral maintenance dose of 200 mg (or 100 mg for patients less than 40 kg) achieves a voriconazole exposure similar to 3 mg/kg IV. A 300 mg (or 150 mg for patients less than 40 kg) oral maintenance dose achieves an exposure similar to 4 mg/kg IV. When the recommended intravenous or oral loading dose regimens are administered, plasma concentrations close to steady state are achieved within the first 24 hours of dosing. Without the loading dose, accumulation occurs during twice daily multiple-dosing with steady-state plasma voriconazole concentrations being achieved by Day 6 in the majority of subjects.
Absorption: Voriconazole is rapidly and almost completely absorbed following oral administration, with maximum plasma concentrations (Cmax) achieved 1-2 hours after dosing. The absolute bioavailability of voriconazole after oral administration is estimated to be 96%. When multiple doses of voriconazole are administered with high fat meals, Cmax and AUCτ are reduced by 34% and 24%, respectively. The absorption of voriconazole is not affected by changes in gastric pH.
Distribution: The volume of distribution at steady state for voriconazole is estimated to be 4.6 l/kg, suggesting extensive distribution into tissues. Plasma protein binding is estimated to be 58%. Cerebrospinal fluid samples from eight patients in a compassionate programme showed detectable voriconazole concentrations in all patients.
Biotransformation: In vitro studies showed that voriconazole is metabolised by the hepatic cytochrome P450 isoenzymes CYP2C19, CYP2C9 and CYP3A4.
The inter-individual variability of voriconazole pharmacokinetics is high.
In vivo studies indicated that CYP2C19 is significantly involved in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism. For example, 15-20% of Asian populations may be expected to be poor metabolisers. For Caucasians, and Blacks the prevalence of poor metabolisers is 3-5%. Studies conducted in Caucasians and Japanese healthy subjects have shown that poor metabolisers have, on average, 4-fold higher voriconazole (AUCτ) than their homozygous extensive metaboliser counterparts. Subjects who are heterozygous extensive metabolisers have on average 2-fold higher voriconazole exposure than their homozygous extensive metaboliser counterparts. The major metabolite of voriconazole is the N-oxide, which accounts for 72% of the circulating radiolabelled metabolites in plasma. This metabolite has minimal antifungal activity and does not contribute to the overall efficacy of voriconazole.
Elimination: Voriconazole is eliminated via hepatic metabolism with less than 2% of the dose excreted unchanged in the urine.
After administration of a radiolabelled dose of voriconazole, approximately 80% of the radioactivity is recovered in the urine after multiple intravenous dosing and 83% in the urine after multiple oral dosing. The majority (>94%) of the total radioactivity is excreted in the first 96 hours after both oral and intravenous dosing.
The terminal half-life of voriconazole depends on dose and is approximately 6 hours at 200 mg (orally). Because of non-linear pharmacokinetics, the terminal half-life is not useful in the prediction of the accumulation or elimination of voriconazole.
Pharmacokinetics in special patient groups: Gender: In an oral multiple-dose study, Cmax and AUCτ for healthy young females were 83% and 113% higher, respectively, than in healthy young males (18-45 years). In the same study, no significant differences in Cmax and AUCτ were observed between healthy elderly males and healthy elderly females (≥65 years).
In the clinical programme, no dose adjustment was made on the basis of gender. The safety profile and plasma concentrations observed in male and female patients were similar. Therefore, no dose adjustment based on gender is necessary.
Elderly: In an oral multiple-dose study Cmax and AUCτ in healthy elderly males (≥65 years) were 61% and 86% higher, respectively, than in healthy young males (18-45 years). No significant differences in Cmax and AUCτ were observed between healthy elderly females (≥65 years) and healthy young females (18-45 years). In the therapeutic studies no dose adjustment was made on the basis of age. A relationship between plasma concentrations and age was observed. The safety profile of voriconazole in young and elderly patients was similar and, therefore, no dose adjustment is necessary for the elderly (see Dosage & Administration).
Paediatric population: The recommended doses in children and adolescent patients are based on a population pharmacokinetic analysis of data obtained from 112 immunocompromised paediatric patients aged 2 to <12 year and 26 immunocompromised adolescent patients aged 12 to <17 years. Multiple intravenous doses of 3, 4, 6, 7 and 8 mg/kg twice daily and multiple oral doses (using the powder for oral suspension) of 4 mg/kg, 6 mg/kg, and 200 mg twice daily were evaluated in 3 paediatric pharmacokinetic studies. Intravenous loading doses of 6 mg/kg IV twice daily on day 1 followed by 4 mg/kg intravenous dose twice daily and 300 mg oral tablets twice daily were evaluated in one adolescent pharmacokinetic study. Larger inter-subject variability was observed in paediatric patients compared to adults.
A comparison of the paediatric and adult population pharmacokinetic data indicated that the predicted total exposure (AUCτ) in children following administration of a 9 mg/kg IV loading dose was comparable to that in adults following a 6 mg/kg IV loading dose. The predicted total exposures in children following IV maintenance doses of 4 and 8 mg/kg twice daily were comparable to those in adults following 3 and 4 mg/kg IV twice daily, respectively. The predicted total exposure in children following an oral maintenance dose of 9 mg/kg (maximum of 350 mg) twice daily was comparable to that in adults following 200 mg oral twice daily. An 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose.
The higher intravenous maintenance dose in paediatric patients relative to adults reflects the higher elimination capacity in paediatric patients due to a greater liver mass to body mass ratio. Oral bioavailability may, however, be limited in paediatric patients with malabsorption and very low body weight for their age. In that case, intravenous voriconazole administration is recommended.
Voriconazole exposures in the majority of adolescent patients were comparable to those in adults receiving the same dosing regimens. However, lower voriconazole exposure was observed in some young adolescents with low body weight compared to adults. It is likely that these subjects may metabolise voriconazole more similarly to children than to adults. Based on the population pharmacokinetic analysis, 12- to 14-year-old adolescents weighing less than 50 kg should receive children's doses (see Dosage & Administration).
Renal impairment: In an oral single-dose (200 mg) study in subjects with normal renal function and mild (creatinine clearnace 41-60 ml/min) to severe (creatinine clearance <20 ml/min) renal impairment, the pharmacokinetics of voriconazole were not significantly affected by renal impairment. The plasma protein binding of voriconazole was similar in subjects with different degrees of renal impairment (see Dosage & Administration and Precautions).
Hepatic impairment: After an oral single-dose (200 mg), AUC was 233% higher in subjects with mild to moderate hepatic cirrhosis (Child-Pugh A and B) compared with subjects with normal hepatic function. Protein binding of voriconazole was not affected by impaired renal function.
In an oral multiple-dose study, AUCτ was similar in subjects with moderate hepatic cirrhosis (Child-Pugh B) given a maintenance dose of 100 mg twice daily and subjects with normal hepatic function given 200 mg twice daily. No pharmacokinetic data are available for patients with severe hepatic cirrhosis (Child-Pugh C) (see Dosage & Administration and Precautions).
Toxicology: Preclinical Safety Data: Repeated-dose toxicity studies with voriconazole indicated the liver to be the target organ. Hepatotoxicity occured at plasma exposures similar to those obtained at therapeutic doses in humans, in common with other antifungal agents. In rats, mice and dogs, voriconazole also induced minimal adrenal changes.
Conventional studies of safety pharmacology, genotoxicity or carcinogenic potential did not reveal a special hazard for humans.
In reproduction studies, voriconazole was shown to be teratogenic in rats and embryotoxic in rabbits at systemic exposures equal to those obtained in humans with therapeutic doses. In the pre- and post-nasal development study in rats at exposures lower than those obtained in humans with therapeutic doses, voriconazole prolonged the duration of gestation and labour and produced dystocia with consequent maternal mortality and reduced perinatal survival of pups. The effects on parturition are probably mediated by species-specific mechanisms, involving reduction of oestradiol levels, and are consistent with those observed with other azole antifungal agents. Voriconazole administration induced no impairment of male or female ferility in rats at exposures similar to those obtained in humans at therapeutic doses.
