Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02 AC03

Mode 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 2425 ng/ml (inter-quartile range 1193 to 4380 ng/ml) and 3742 ng/ml (inter-quartile range 2027 to 6302 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 all Aspergillus species tested. In addition voriconazole shows in vitro 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., Coccidioides immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum, Exophiala spinifera, Fonsecaea pedrosoi, Madurella mycetomatis, Paecilomyces lilacinus, Penicillium spp. including P. marneffei, Phialophora richardsiae, Scopulariopsis brevicaulis and Trichosporon spp.
including T. beigelii infections.

In vitro activity 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 are 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).

EUCAST Breakpoints

Candida and Aspergillus species                              Minimal Inhibitory Concentration (MIC) breakpoint (mg/L)
≤S (Susceptible)         >R (Resistant)
Candida albicans1                                                  0.06                    0.25 Candida dubliniensis1                                               0.06                       0.25 Candida glabrata                                          Insufficient evidence (IE)            IE Candida krusei                                                       IE                         IE 1
Candida parapsilosis                                                0.125                      0.25 Candida tropicalis1                                                 0.125                      0.25 Candida guilliermondii2                                              IE                         IE Non-species related breakpoints for Candida3                         IE                         IE 4
Aspergillus fumigatus                                                 1                          1 Aspergillus nidulans4                                                 1                          1 Aspergillus flavus                                                   IE5                        IE5 Aspergillus niger                                                    IE5                        IE5 Aspergillus terreus                                                  IE5                        IE5 Non-species related breakpoints6                                     IE                          IE 1
Strains with MIC values above the Susceptible/Intermediate (S/I) breakpoint are rare or not yet reported. The identification and antifungal susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed isolates with MIC above the current resistant breakpoint they should be reported resistant. A clinical response of 76% was achieved in infections caused by the species listed below when MICs were lower than or equal to the epidemiological cut-offs. Therefore, wild type populations of C.
albicans, C. dubliniensis, C. parapsilosis and C. tropicalis are considered susceptible.
2
The epidemiological cut-off values (ECOFFs) for these species are in general higher than for C.
albicans.
3
Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific Candida species. They are for use only for organisms that do not have specific breakpoints.
4
Area of technical uncertainty (ATU) is 2. Report as R with the following comment: "In some clinical situations (non-invasive infections forms) voriconazole can be used provided sufficient exposure is 
ensured".
5
The ECOFFs for these species are in general one two-fold dilution higher than for A. fumigatus.
6
Non-species related breakpoints have not been determined.

Clinical 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 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 significantly higher than that for the comparator and a clinically and 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 amphotericin 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.

Timepoint                                    Voriconazole               Amphotericin B → fluconazole (N=248)                            (N=122)

EOT                                            178 (72%)                           88 (72%) 2 weeks after EOT                              125 (50%)                           62 (51%)
6 weeks after EOT                              104 (42%)                           55 (45%) 12 weeks after EOT                             104 (42%)                           51 (42%) 
Serious 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) infections. 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.: Successful 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.

Primary Prophylaxis of Invasive Fungal Infections – Efficacy in HSCT recipients without prior proven or probable IFI
Voriconazole was compared to itraconazole as primary prophylaxis in an open-label, comparative, multicenter study of adult and adolescent allogeneic HSCT recipients without prior proven or probable IFI. Success was defined as the ability to continue study drug prophylaxis for 100 days after HSCT (without stopping for >14 days) and survival with no proven or probable IFI for 180 days after HSCT.
The modified intent-to-treat (MITT) group included 465 allogeneic HSCT recipients with 45% of patients having AML. From all patients 58% were subject to myeloablative conditions regimens.
Prophylaxis with study drug was started immediately after HSCT: 224 received voriconazole and 241 received itraconazole. The median duration of study drug prophylaxis was 96 days for voriconazole and 68 days for itraconazole in the MITT group.

Success rates and other secondary endpoints are presented in the table below: 
Study Endpoints                     Voriconazole       Itraconazole         Difference in          P-Value N=224              N=241            proportions and the
95% confidence interval (CI)
Success at day 180*                 109 (48.7%)        80 (33.2%)      16.4% (7.7%, 25.1%)**       0.0002** Success at day 100                  121 (54.0%)        96 (39.8%)      15.4% (6.6%, 24.2%)**       0.0006** Completed at least 100 days of      120 (53.6%)        94 (39.0%)       14.6% (5.6%, 23.5%)         0.0015 study drug prophylaxis
Survived to day 180                 184 (82.1%)        197 (81.7%)       0.4% (-6.6%, 7.4%)            0.9107 Developed proven or probable        3 (1.3%)           5 (2.1%)          -0.7% (-3.1%, 1.6%)           0.5390 IFI to day 180
Developed proven or probable      2 (0.9%)          4 (1.7%)           -0.8% (-2.8%, 1.3%)           0.4589 IFI to day 100
Developed proven or probable      0                 3 (1.2%)           -1.2% (-2.6%, 0.2%)           0.0813 IFI while on study drug
* Primary endpoint of the study
** Difference in proportions, 95% CI and p-values obtained after adjustment for randomization 
The breakthrough IFI rate to Day 180 and the primary endpoint of the study, which is Success at Day 180, for patients with AML and myeloablative conditioning regimens respectively, is presented in the table below:

AML

Study endpoints                     Voriconazole         Itraconazole       Difference in proportions and (N=98)               (N=109)             the 95% confidence interval
(CI)
Breakthrough IFI – Day 180          1 (1.0%)             2 (1.8%)          -0.8% (-4.0%, 2.4%) ** 
Success at Day 180*                 55 (56.1%)           45 (41.3%)        14.7% (1.7%, 27.7%)*** 
* Primary endpoint of study
** Using a margin of 5%, non inferiority is demonstrated
***Difference in proportions, 95% CI obtained after adjustment for randomization 

Myeloablative conditioning regimens
Study endpoints                    Voriconazole         Itraconazole     Difference in proportions and the (N=125)              (N=143)            95% confidence interval (CI)

Breakthrough IFI – Day 180         2 (1.6%)             3 (2.1%)        -0.5% (-3.7%, 2.7%) ** 
Success at Day 180*                70 (56.0%)           53 (37.1%)      20.1% (8.5%, 31.7%)*** 
* Primary endpoint of study
** Using a margin of 5%, non inferiority is demonstrated
*** Difference in proportions, 95% CI obtained after adjustment for randomization 
Secondary Prophylaxis of IFI – Efficacy in HSCT recipients with prior proven or probable IFI Voriconazole was investigated as secondary prophylaxis in an open-label, non-comparative, multicenter study of adult allogeneic HSCT recipients with prior proven or probable IFI. The primary endpoint was the rate of occurrence of proven and probable IFI during the first year after HSCT. The MITT group included 40 patients with prior IFI, including 31 with aspergillosis, 5 with candidiasis, and 4 with other IFI. The median duration of study drug prophylaxis was 95.5 days in the MITT group.

Proven or probable IFIs developed in 7.5% (3/40) of patients during the first year after HSCT, including one candidemia, one scedosporiosis (both relapses of prior IFI), and one zygomycosis. The survival rate at Day 180 was 80.0% (32/40) and at 1 year was 70.0% (28/40).

Duration of treatment
In clinical trials, 705 patients received voriconazole therapy for greater than 12 weeks, with 164 patients receiving voriconazole for over 6 months.

Paediatric population
Fifty-three paediatric patients aged 2 to <18 years were treated with voriconazole in two prospective, open-label, non-comparative, multi-center clinical trials. One study enrolled 31 patients with possible, proven or probable invasive aspergillosis (IA), of whom 14 patients had proven or probable IA and were included in the MITT efficacy analyses. The second study enrolled 22 patients with invasive candidiasis including candidaemia (ICC), and esophageal candidiasis (EC) requiring either primary or salvage therapy, of whom 17 were included in the MITT efficacy analyses. For patients with IA the overall rates of global response at 6 weeks were 64.3% (9/14), the global response rate was 40% (2/5) for patients 2 to <12 years and 77.8% (7/9) for patients 12 to <18 years of age. For patients with ICC the global response rate at EOT was 85.7% (6/7) and for patients with EC the global response rate at EOT was 70% (7/10). The overall rate of response (ICC and EC combined) was 88.9% (8/9) for 2 to <12 years old and 62.5% (5/8) for 12 to <18 years old.

Clinical studies examining QTc interval
A placebo-controlled, randomized, single-dose, crossover study to evaluate the effect on the QTc interval of healthy volunteers was conducted with three oral doses of voriconazole and ketoconazole.
The placebo-adjusted mean maximum increases in QTc from baseline after 800, 1200 and 1600 mg of voriconazole were 5.1, 4.8, and 8.2 msec, respectively, and 7.0 msec for ketoconazole 800 mg. No subject in any group had an increase in QTc of ≥60 msec from baseline. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

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.

Powder for oral suspension
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%.
Bioequivalence was established between the 200 mg tablet and the 40mg/ml oral suspension when administered as a 200 mg dose. When multiple doses of voriconazole are administered with high fat 

meals, Cmax and AUCτ are reduced by 58% and 37%, 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 Caucasian and Japanese healthy subjects have shown that poor metabolisers have, on average, 4-fold higher voriconazole exposure (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 dosage adjustment was made on the basis of gender. The safety profile and plasma concentrations observed in male and female patients were similar. Therefore, no dosage 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 dosage 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 dosage adjustment is necessary for the elderly (see section 4.2).

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 years 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 metabolize 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 section 4.2).

Renal impairment
Film-coated tablets:
In an oral single dose (200 mg) study in subjects with normal renal function and mild (creatinine clearance 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 sections 4.2 and 4.4).

Powder for solution for infusion:
In patients with moderate to severe renal dysfunction (serum creatinine levels > 2.5 mg/dl), accumulation of the intravenous vehicle, SBECD, occurs (see sections 4.2 and 4.4).

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 hepatic 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 sections 4.2 and 4.4).