Pharmacokinetics
General Pharmacokinetic Characteristics
The pharmacokinetics of voriconazole have been characterized in healthy subjects,
special populations and patients.
The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism.
The interindividual variability of voriconazole pharmacokinetics is high. Greater
than proportional increase in exposure is observed with increasing dose. It
is estimated that, on average, increasing the oral dose in healthy subjects from
200 mg Q12h to 300 mg Q12h leads to a 2.5-fold increase in exposure (AUCτ),
while increasing the intravenous dose from 3 mg/kg Q12h to 4 mg/kg Q12h produces
a 2.3-fold increase in exposure (Table 1).
Table 1
Population Pharmacokinetic Parameters of Voriconazole in Subjects
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 hematopoietic tissue), the observed pharmacokinetic characteristics were similar
to those observed in healthy subjects (Table 2).
Table 2
Pharmacokinetic Parameters of Voriconazole in Patients at Risk for Aspergillosis
Sparse plasma sampling for pharmacokinetics was conducted in the therapeutic studies
in patients aged 12-18 years. In 11 adolescent patients who received a mean voriconazole
maintenance dose of 4 mg/kg IV, the median of the calculated mean plasma concentrations
was 1.60 μg/mL (inter-quartile range 0.28 to
2.73 μg/mL). In 17 adolescent patients for whom mean plasma concentrations were
calculated following a mean oral maintenance dose of 200 mg Q12h, the median of
the calculated mean plasma concentrations was 1.16 μg/mL (inter-quartile range 0.85
to 2.14 μg/mL).
When the recommended intravenous or oral loading dose regimens are administered
to healthy subjects, peak 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 peak plasma voriconazole concentrations
being achieved by day 6 in the majority of subjects (Table 3).
Table 3
Pharmacokinetic Parameters of Voriconazole from Loading Dose and Maintenance Dose
Regimens (Individual Studies in Subjects)
Steady state trough plasma concentrations with voriconazole are achieved after approximately
5 days of oral or intravenous dosing without a loading dose regimen. However, when
an intravenous loading dose regimen is used, steady state trough plasma concentrations
are achieved within 1 day.
Absorption
The pharmacokinetic properties of voriconazole are similar following administration
by the intravenous and oral routes. Based on a population pharmacokinetic analysis
of pooled data in healthy subjects (N=207), the oral bioavailability of voriconazole
is estimated to be 96% (CV 13%). Bioequivalence was established between the
200 mg tablet and the 40 mg/mL oral suspension when administered as a 400 mg
Q12h loading dose followed by a 200 mg Q12h maintenance dose.
Maximum plasma concentrations (Cmax) are achieved 1-2
hours after dosing. When multiple doses of voriconazole are administered with high-fat
meals, the mean Cmax and AUCτ
are reduced by 34% and 24%, respectively when administered as a tablet and by 58%
and 37% respectively when administered as the oral suspension (see DOSAGE AND ADMINISTRATION).
In healthy subjects, the absorption of voriconazole is not affected by coadministration
of oral ranitidine, cimetidine, or omeprazole, drugs that are known to increase
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% and was shown to be independent of plasma concentrations
achieved following single and multiple oral doses of 200 mg or 300 mg (approximate
range: 0.9-15 μg/mL). Varying degrees of hepatic and renal insufficiency do not
affect the protein binding of voriconazole.
Metabolism
In vitro studies showed that voriconazole is metabolized by the human hepatic
cytochrome P450 enzymes, CYP2C19, CYP2C9 and CYP3A4 (see CLINICAL PHARMACOLOGY –
Drug Interactions).
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 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.
The major metabolite of voriconazole is the N-oxide, which accounts for 72% of the
circulating radiolabelled metabolites in plasma. Since this metabolite has minimal
antifungal activity, it does not contribute to the overall efficacy of voriconazole.
Excretion
Voriconazole is eliminated via hepatic metabolism with less than 2% of the dose
excreted unchanged in the urine. After administration of a single radiolabelled
dose of either oral or IV voriconazole, preceded by multiple oral or IV dosing,
approximately 80% to 83% of the radioactivity is recovered in the urine. The majority
(>94%) of the total radioactivity is excreted in the first 96 hours after both
oral and intravenous dosing.
As a result of non-linear pharmacokinetics, the terminal half-life of voriconazole
is dose dependent and therefore not useful in predicting the accumulation or elimination
of voriconazole.
Pharmacokinetic-Pharmacodynamic Relationships
Clinical Efficacy and Safety
In 10 clinical trials, the median values for the average and maximum voriconazole
plasma concentrations in individual patients across these studies (N=1121) was 2.51
μg/mL (inter-quartile range 1.21 to 4.44 μg/mL) and 3.79 μg/mL (inter-quartile range
2.06 to 6.31 μg/mL), respectively. A pharmacokinetic-pharmacodynamic analysis of
patient data from 6 of these 10 clinical trials (N=280) could not detect a positive
association between mean, maximum or minimum plasma voriconazole concentration and
efficacy. However, PK/PD analyses of the data from all 10 clinical trials identified
positive associations between plasma voriconazole concentrations and rate of both
liver function test abnormalities and visual disturbances (see ADVERSE REACTIONS).
Electrocardiogram
A placebo-controlled, randomized, crossover study to evaluate the effect on the
QT interval of healthy male and female subjects was conducted with three single
oral doses of voriconazole and ketoconazole. Serial ECGs and plasma samples were
obtained at specified intervals over a 24-hour post dose observation period. The
placebo-adjusted mean maximum increases in QTc from baseline after 800, 1200 and
1600 mg of voriconazole and after ketoconazole 800 mg were all <10 msec. Females
exhibited a greater increase in QTc than males, although all mean changes were <10
msec. Age was not found to affect the magnitude of increase in QTc. 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. However, the QT effect of voriconazole combined with drugs known to prolong
the QT interval is unknown (see CONTRAINDICATIONS, PRECAUTIONS–Drug Interactions).
Pharmacokinetics in Special Populations
Gender
In a multiple oral dose study, the mean Cmax and AUCτ
for healthy young females were 83% and 113% higher, respectively, than in healthy
young males
(18-45 years), after tablet dosing. In the same study, no significant differences
in the mean Cmax and AUCτ were
observed between healthy elderly males and healthy elderly females (≥65 years).
In a similar study, after dosing with the oral suspension, the mean AUC for healthy
young females was 45% higher than in healthy young males whereas the mean Cmax
was comparable between genders. The steady state trough voriconazole concentrations
(Cmin) seen in females were 100% and 91% higher than in
males receiving the tablet and the oral suspension, respectively.
In the clinical program, no dosage adjustment was made on the basis of gender. The
safety profile and plasma concentrations observed in male and female subjects were
similar. Therefore, no dosage adjustment based on gender is necessary.
Geriatric
In an oral multiple dose study the mean Cmax and AUCτ
in healthy elderly males
(≥65 years) were 61% and 86% higher, respectively, than in young males
(18-45 years). No significant differences in the mean Cmax
and AUCτ were observed between healthy elderly females
(≥65 years) and healthy young females
(18-45 years).
In the clinical program, no dosage adjustment was made on the basis of age. An analysis
of pharmacokinetic data obtained from 552 patients from 10 voriconazole clinical
trials showed that the median voriconazole plasma concentrations in the elderly
patients (>65 years) were approximately 80% to 90% higher than those in the younger
patients (≤65 years) after either IV or oral administration. However, the safety
profile of voriconazole in young and elderly subjects was similar and, therefore,
no dosage adjustment is necessary for the elderly.
Pediatric
A population pharmacokinetic analysis was conducted on pooled data from
35 immunocompromised pediatric patients aged 2 to <12 years old who were included
in two pharmacokinetic studies of intravenous voriconazole (single dose and multiple
dose). Twenty-four of these patients received multiple intravenous maintenance doses
of 3 mg/kg and 4 mg/kg. A comparison of the pediatric and adult population pharmacokinetic
data revealed that the predicted average steady state plasma concentrations were
similar at the maintenance dose of 4 mg/kg every 12 hours in children and 3 mg/kg
every 12 hours in adults (medians of 1.19 μg/mL and 1.16 μg/mL in children and adults,
respectively) (see PRECAUTIONS, Pediatric Use).
Hepatic Insufficiency
After a single oral dose (200 mg) of voriconazole in 8 patients with mild (Child-Pugh
Class A) and 4 patients with moderate (Child-Pugh Class B) hepatic insufficiency,
the mean systemic exposure (AUC) was 3.2-fold higher than in age and weight matched
controls with normal hepatic function. There was no difference in mean peak plasma
concentrations (Cmax) between the groups. When only the
patients with mild (Child-Pugh Class A) hepatic insufficiency were compared to controls,
there was still a 2.3-fold increase in the mean AUC in the group with hepatic insufficiency
compared to controls.
In an oral multiple dose study, AUCτ was similar in 6
subjects with moderate hepatic impairment (Child-Pugh Class B) given a lower maintenance
dose of 100 mg twice daily compared to 6 subjects with normal hepatic function given
the standard
200 mg twice daily maintenance dose. The mean peak plasma concentrations (Cmax)
were 20% lower in the hepatically impaired group.
It is recommended that the standard loading dose regimens be used but that the maintenance
dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class
A and B) receiving voriconazole. No pharmacokinetic data are available for patients
with severe hepatic cirrhosis (Child-Pugh Class C) (see DOSAGE AND ADMINISTRATION).
Renal Insufficiency
In a single oral dose (200 mg) study in 24 subjects with normal renal function and
mild to severe renal impairment, systemic exposure (AUC) and peak plasma concentration
(Cmax) of voriconazole were not significantly affected
by renal impairment. Therefore, no adjustment is necessary for oral dosing
in patients with mild to severe renal impairment.
In a multiple dose study of IV voriconazole (6 mg/kg IV loading dose x 2, then
3 mg/kg IV x 5.5 days) in 7 patients with moderate renal dysfunction (creatinine
clearance 30-50 mL/min), the systemic exposure (AUC) and peak plasma concentrations
(Cmax) were not significantly different from those in
6 subjects with normal renal function.
However, in patients with moderate renal dysfunction (creatinine clearance
30-50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. The mean
systemic exposure (AUC) and peak plasma concentrations (Cmax)
of SBECD were increased 4-fold and almost 50%, respectively, in the moderately impaired
group compared to the normal control group.
Intravenous voriconazole should be avoided in patients with moderate or severe renal
impairment (creatinine clearance <50 mL/min), unless an assessment of the benefit/risk
to the patient justifies the use of intravenous voriconazole (see DOSAGE AND ADMINISTRATION
– Dosage Adjustment).
A pharmacokinetic study in subjects with renal failure undergoing hemodialysis showed
that voriconazole is dialyzed with clearance of 121 mL/min. The intravenous vehicle,
SBECD, is hemodialyzed with clearance of 55 mL/min. A 4-hour hemodialysis session
does not remove a sufficient amount of voriconazole to warrant dose adjustment.
Drug Interactions
Effects of Other Drugs on Voriconazole
Voriconazole is metabolized by the human hepatic cytochrome P450 enzymes CYP2C19,
CYP2C9, and CYP3A4. Results of in vitro metabolism studies indicate that
the affinity of voriconazole is highest for CYP2C19, followed by CYP2C9, and is
appreciably lower for CYP3A4. Inhibitors or inducers of these three enzymes may
increase or decrease voriconazole systemic exposure (plasma concentrations), respectively.
The systemic exposure to voriconazole is significantly
reduced or is expected to be reduced by the concomitant
administration of the following agents and their use is
contraindicated:
Rifampin (potent CYP450 inducer): Rifampin (600 mg once daily) decreased
the steady state Cmax and AUCτ
of voriconazole (200 mg Q12h x 7 days) by an average of 93% and 96%, respectively,
in healthy subjects. Doubling the dose of voriconazole to 400 mg Q12h does not restore
adequate exposure to voriconazole during coadministration with rifampin.
Coadministration of voriconazole and rifampin is contraindicated (see CONTRAINDICATIONS,
PRECAUTIONS - Drug Interactions).
Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate):
The effect of the coadministration of voriconazole and ritonavir (400 mg and 100
mg) was investigated in two separate studies. High-dose ritonavir (400 mg Q12h for
9 days) decreased the steady state Cmax and AUCτ
of oral voriconazole (400 mg Q12h for
1 day, then 200 mg Q12h for 8 days) by an average of 66% and 82%, respectively,
in healthy subjects. Low-dose ritonavir (100 mg Q12h for 9 days) decreased the steady
state Cmax and AUCτ of oral
voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 8 days) by an average
of 24% and 39%, respectively, in healthy subjects. Although repeat oral administration
of voriconazole did not have a significant effect on steady state Cmax
and AUCτ of high-dose ritonavir in healthy subjects, steady
state Cmax and AUCτ of low-dose
ritonavir decreased slightly by 24% and 14% respectively, when administered concomitantly
with oral voriconazole in healthy subjects. Coadministration of voriconazole and
high-dose ritonavir (400 mg Q12h) is contraindicated. Coadministration of voriconazole
and low-dose ritonavir (100 mg Q12h) should be avoided, unless an assessment of
the benefit/risk to the patient justifies the use of voriconazole (see CONTRAINDICATIONS,
PRECAUTIONS – Drug Interactions).
St. John’s Wort (CYP450 inducer; P-gp inducer): In an independent published study in healthy volunteers who were
given multiple oral doses of St. John’s Wort (300 mg LI 160 extract three times daily for 15 days) followed by a single 400 mg oral
dose of voriconazole, a 59% decrease in mean voriconazole AUC0-∞ was observed. In contrast, coadministration of single oral doses of
St. John’s Wort and voriconazole had no appreciable effect on voriconazole AUC0-∞. Because long-term use of St. John’s Wort could lead to
reduced voriconazole exposure, concomitant use of voriconazole with St. John’s Wort is contraindicated (see CONTRAINDICATIONS).
Carbamazepine and long-acting barbiturates (potent CYP450 inducers):
Although not studied in vitro or in vivo, carbamazepine and long-acting
barbiturates (e.g., phenobarbital, mephobarbital) are likely to significantly decrease
plasma voriconazole concentrations. Coadministration of voriconazole with carbamazepine
or long-acting barbiturates is contraindicated (see CONTRAINDICATIONS, PRECAUTIONS
– Drug Interactions).
Minor or no significant pharmacokinetic interactions that do not require dosage
adjustment:
Cimetidine(non-specific CYP450 inhibitor and increases gastric pH):
Cimetidine (400 mg Q12h x 8 days) increased voriconazole steady state Cmax
and AUCτ by an average of 18% (90% CI: 6%, 32%) and 23%
(90% CI: 13%, 33%), respectively, following oral doses of 200 mg Q12h x 7 days to
healthy subjects.
Ranitidine (increases gastric pH): Ranitidine (150 mg Q12h) had no
significant effect on voriconazole Cmax and AUCτ
following oral doses of 200 mg Q12h x 7 days to healthy subjects.
Macrolide antibiotics: Coadministration of erythromycin (CYP3A4
inhibitor; 1g Q12h for 7 days) or azithromycin (500 mg qd for 3 days) with
voriconazole 200 mg Q12h for 14 days had no significant effect on voriconazole steady
state Cmax and AUCτ in healthy
subjects. The effects of voriconazole on the pharmacokinetics of either erythromycin
or azithromycin are not known.
Effects of Voriconazole on Other Drugs
In vitro studies with human hepatic microsomes show that voriconazole inhibits
the metabolic activity of the cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4.
In these studies, the inhibition potency of voriconazole for CYP3A4 metabolic activity
was significantly less than that of two other azoles, ketoconazole and itraconazole.
In vitro studies also show that the major metabolite of voriconazole, voriconazole
N-oxide, inhibits the metabolic activity of CYP2C9 and CYP3A4 to a greater extent
than that of CYP2C19. Therefore, there is potential for voriconazole and its major
metabolite to increase the systemic exposure (plasma concentrations) of other drugs
metabolized by these CYP450 enzymes.
The systemic exposure of the following drugs is significantly increased or is
expected to be significantly increased by coadministration of voriconazole and their use is contraindicated:
Sirolimus (CYP3A4 substrate): Repeat dose administration of oral voriconazole
(400 mg Q12h for 1 day, then 200 mg Q12h for 8 days) increased the Cmax
and AUC of sirolimus (2 mg single dose) an average of 7-fold (90% CI: 5.7, 7.5)
and 11-fold (90% CI: 9.9, 12.6), respectively, in healthy male subjects. Coadministration
of voriconazole and sirolimus is contraindicated (see CONTRAINDICATIONS, PRECAUTIONS – Drug Interactions).
Terfenadine, astemizole, cisapride, pimozide and quinidine (CYP3A4 substrates):
Although not studied in vitro or in vivo, concomitant administration
of voriconazole with terfenadine, astemizole, cisapride, pimozide or quinidine may
result in inhibition of the metabolism of these drugs. Increased plasma concentrations
of these drugs can lead to QT prolongation and rare occurrences of torsade de pointes.
Coadministration of voriconazole and terfenadine, astemizole, cisapride, pimozide
and quinidine is contraindicated (see CONTRAINDICATIONS, PRECAUTIONS – Drug
Interactions).
Ergot alkaloids: Although not studied in vitro or in vivo,
voriconazole may increase the plasma concentration of ergot alkaloids (ergotamine
and dihydroergotamine) and lead to ergotism. Coadministration of voriconazole with
ergot alkaloids is contraindicated (see CONTRAINDICATIONS, PRECAUTIONS –
Drug Interactions).
Coadministration of voriconazole with the following agents results in increased
exposure or is expected to result in increased exposure to these drugs. Therefore,
careful monitoring and/or dosage adjustment of these drugs is needed:
Alfentanil (CYP3A4 substrate): Coadministration of multiple doses of oral voriconazole (400
mg q12h on day 1, 200 mg q12h on day 2) with a single 20 mcg/kg intravenous dose of alfentanil
with concomitant naloxone resulted in a 6-fold increase in mean alfentanil AUC0-∞ and a 4-fold
prolongation of mean alfentanil elimination half-life, compared to when alfentanil was given
alone. An increase in the incidence of delayed and persistent alfentanil-associated nausea and
vomiting during co-administration of voriconazole and alfentanil was also observed. Reduction
in the dose of alfentanil or other opiates that are also metabolized by CYP3A4 (e.g., sufentanil), and extended close monitoring of patients for respiratory and other opiate-associated adverse events, may be necessary when any of these opiates is coadministered with voriconazole. (see PRECAUTIONS – Drug Interactions).
Cyclosporine (CYP3A4 substrate): In stable renal transplant recipients
receiving chronic cyclosporine therapy, concomitant administration of oral voriconazole
(200 mg Q12h for 8 days) increased cyclosporine Cmax and
AUCτ an average of
1.1 times (90% CI: 0.9, 1.41) and 1.7 times (90% CI: 1.5, 2.0), respectively, as
compared to when cyclosporine was administered without voriconazole. When initiating
therapy with voriconazole in patients already receiving cyclosporine, it is recommended
that the cyclosporine dose be reduced to one-half of the original dose and followed
with frequent monitoring of the cyclosporine blood levels. Increased cyclosporine
levels have been associated with nephrotoxicity. When voriconazole is discontinued,
cyclosporine levels should be frequently monitored and the dose increased as necessary
(see PRECAUTIONS – Drug Interactions).
Methadone (CYP3A4, CYP2C19, CYP2C9 substrate): Repeat dose administration
of oral voriconazole (400mg Q12h for 1 day, then 200mg Q12h for 4 days) increased
the Cmax and AUCτ of pharmacologically
active R-methadone by 31% (90% CI: 22%, 40%) and 47% (90% CI: 38%, 57%), respectively,
in subjects receiving a methadone maintenance dose (30-100 mg QD). The Cmax
and AUC of (S)-methadone increased by 65% (90% CI: 53%, 79%) and 103% (90% CI: 85%,
124%), respectively. Increased plasma concentrations of methadone have been associated
with toxicity including QT prolongation. Frequent monitoring for adverse events
and toxicity related to methadone is recommended during coadministration. Dose reduction
of methadone may be needed (see PRECAUTIONS – Drug Interactions).
Tacrolimus (CYP3A4 substrate): Repeat oral dose administration of
voriconazole (400 mg Q12h x 1 day, then 200 mg Q12h x 6 days) increased tacrolimus
(0.1 mg/kg single dose) Cmax and AUCτ
in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI:
2.7, 3.8), respectively. When initiating therapy with voriconazole in patients already
receiving tacrolimus, it is recommended that the tacrolimus dose be reduced to one-third
of the original dose and followed with frequent monitoring of the tacrolimus blood
levels. Increased tacrolimus levels have been associated with nephrotoxicity. When
voriconazole is discontinued, tacrolimus levels should be carefully monitored and
the dose increased as necessary (see PRECAUTIONS – Drug Interactions).
Warfarin (CYP2C9 substrate): Coadministration of voriconazole (300
mg Q12h x 12 days) with warfarin (30 mg single dose) significantly increased maximum prothrombin
time by approximately 2 times that of placebo in healthy subjects. Close monitoring
of prothrombin time or other suitable anticoagulation tests is recommended if warfarin
and voriconazole are coadministered and the warfarin dose adjusted accordingly (see
PRECAUTIONS - Drug Interactions).
Oral Coumarin Anticoagulants (CYP2C9, CYP3A4 substrates): Although
not studied in vitro or in vivo, voriconazole may increase the plasma
concentrations of coumarin anticoagulants and therefore may cause an increase in
prothrombin time. If patients receiving coumarin preparations are treated simultaneously
with voriconazole, the prothrombin time or other suitable anticoagulation tests
should be monitored at close intervals and the dosage of anti-coagulants adjusted
accordingly (see PRECAUTIONS – Drug Interactions).
Statins (CYP3A4 substrates): Although not studied clinically, voriconazole
has been shown to inhibit lovastatin metabolism in vitro (human liver microsomes).
Therefore, voriconazole is likely to increase the plasma concentrations of statins
that are metabolized by CYP3A4. It is recommended that dose adjustment of the statin
be considered during coadministration. Increased statin concentrations in plasma
have been associated with rhabdomyolysis (see PRECAUTIONS – Drug Interactions).
Benzodiazepines (CYP3A4 substrates): Although not studied clinically,
voriconazole has been shown to inhibit midazolam metabolism in vitro (human
liver microsomes). Therefore, voriconazole is likely to increase the plasma concentrations
of benzodiazepines that are metabolized by CYP3A4 (e.g., midazolam, triazolam, and
alprazolam) and lead to a prolonged sedative effect. It is recommended that dose
adjustment of the benzodiazepine be considered during coadministration (see PRECAUTIONS
– Drug Interactions).
Calcium Channel Blockers (CYP3A4 substrates): Although not studied
clinically, voriconazole has been shown to inhibit felodipine metabolism in vitro
(human liver microsomes). Therefore, voriconazole may increase the plasma concentrations
of calcium channel blockers that are metabolized by CYP3A4. Frequent monitoring
for adverse events and toxicity related to calcium channel blockers is recommended
during coadministration. Dose adjustment of the calcium channel blocker may be needed
(see PRECAUTIONS – Drug Interactions).
Sulfonylureas (CYP2C9 substrates): Although not studied in vitro
or in vivo, voriconazole may increase plasma concentrations of sulfonylureas
(e.g., tolbutamide, glipizide, and glyburide) and therefore cause hypoglycemia.
Frequent monitoring of blood glucose and appropriate adjustment (i.e., reduction)
of the sulfonylurea dosage is recommended during coadministration (see PRECAUTIONS
– Drug Interactions).
Vinca Alkaloids (CYP3A4 substrates): Although not studied in vitro
or in vivo, voriconazole may increase the plasma concentrations of the vinca
alkaloids (e.g., vincristine and vinblastine) and lead to neurotoxicity. Therefore,
it is recommended that dose adjustment of the vinca alkaloid be considered.
No significant pharmacokinetic interactions were observed when voriconazole was
coadministered with the following agents. Therefore, no dosage adjustment for these
agents is recommended:
Prednisolone (CYP3A4 substrate): Voriconazole (200 mg Q12h x 30 days)
increased Cmax and AUC of prednisolone (60 mg single dose)
by an average of 11% and 34%, respectively, in healthy subjects.
Digoxin (P-glycoprotein mediated transport): Voriconazole (200 mg
Q12h x
12 days) had no significant effect on steady state Cmax
and AUCτ of digoxin
(0.25 mg once daily for 10 days) in healthy subjects.
Mycophenolic acid (UDP-glucuronyl transferase substrate): Voriconazole
(200 mg Q12h x 5 days) had no significant effect on the Cmax
and AUCτ of mycophenolic acid and its major metabolite,
mycophenolic acid glucuronide after administration of a 1 g single oral dose of
mycophenolate mofetil.
Two-Way Interactions
Concomitant use of the following agents with voriconazole is contraindicated:
Rifabutin (potent CYP450 inducer): Rifabutin (300 mg once daily) decreased
the Cmax and AUCτ of voriconazole
at 200 mg twice daily by an average of 67% (90% CI: 58%, 73%) and 79% (90% CI: 71%,
84%), respectively, in healthy subjects. During coadministration with rifabutin
(300 mg once daily), the steady state Cmax and AUCτ
of voriconazole following an increased dose of 400 mg twice daily were on average
approximately 2 times higher, compared with voriconazole alone at 200 mg twice daily.
Coadministration of voriconazole at 400 mg twice daily with rifabutin 300 mg twice
daily increased the Cmax and AUCτ
of rifabutin by an average of 3 times (90% CI: 2.2, 4.0) and 4 times (90% CI: 3.5,
5.4), respectively, compared to rifabutin given alone. Coadministration of voriconazole
and rifabutin is contraindicated.
Significant drug interactions that may require dosage adjustment, frequent monitoring
of drug levels and/or frequent monitoring of drug-related adverse events/toxicity:
Efavirenz, a non-nucleoside reverse transcriptase inhibitor (CYP450 inducer; CYP3A4
inhibitor and substrate): Standard doses of voriconazole and standard doses of efavirenz must
not be coadministered (see PRECAUTIONS – Drug Interactions). Steady state efavirenz (400 mg PO QD)
decreased the steady state Cmax and AUCτ of voriconazole (400 mg PO Q12h for 1 day, then
200 mg PO Q12h for 8 days) by an average of 61% and 77%, respectively, in healthy male subjects.
Voriconazole at steady state (400 mg PO Q12h for 1 day, then 200 mg Q12h for 8 days) increased the
steady state Cmax and AUCτ of efavirenz (400 mg PO QD for 9 days) by an average of 38%
and 44%, respectively, in healthy subjects.
The pharmacokinetics of adjusted doses of voriconazole and efavirenz were studied in healthy
male subjects following administration of voriconazole (400 mg PO Q12h on Days 2 to 7) with
efavirenz (300 mg PO Q24h on Days 1-7), relative to steady-state administration of voriconazole
(400 mg for 1 day, then 200 mg PO Q12h for 2 days) or efavirenz (600 mg Q24h for 9 days).
Coadministration of voriconazole 400 mg Q 12h with efavirenz 300 mg Q24h, decreased
voriconazole AUCτ by 7% (90% CI: -23%, 13%) and increased Cmax by 23% (90% CI: -1%,
53%); efavirenz AUCτ was increased by 17% (90% CI: 6%, 29%) and Cmax was equivalent.
Voriconazole may be coadministered with efavirenz if the voriconazole maintenance dose is
increased to 400 mg Q12h and the efavirenz dose is decreased to 300 mg Q24h. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored.
Phenytoin (CYP2C9 substrate and potent CYP450 inducer): Repeat dose
administration of phenytoin (300 mg once daily) decreased the steady state Cmax
and AUCτ of orally administered voriconazole (200 mg Q12h
x 14 days) by an average of 50% and 70%, respectively, in healthy subjects. Administration
of a higher voriconazole dose (400 mg Q12h x 7 days) with phenytoin (300 mg once
daily) resulted in comparable steady state voriconazole Cmax
and AUCτ estimates as compared to when voriconazole was
given at 200 mg Q12h without phenytoin.
Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole
is increased from 4 mg/kg to 5 mg/kg intravenously every 12 hours or from 200 mg
to 400 mg orally, every 12 hours (100 mg to 200 mg orally, every
12 hours in patients less than 40 kg) (see DOSAGE AND ADMINISTRATION).
Repeat dose administration of voriconazole (400 mg Q12h x 10 days) increased the
steady state Cmax and AUCτ of
phenytoin (300 mg once daily) by an average of 70% and 80%, respectively, in healthy
subjects. The increase in phenytoin Cmax and AUC when
coadministered with voriconazole may be expected to be as high as 2 times the Cmax
and AUC estimates when phenytoin is given without voriconazole. Therefore, frequent
monitoring of plasma phenytoin concentrations and phenytoin-related adverse effects
is recommended when phenytoin is coadministered with voriconazole (see PRECAUTIONS
– Drug Interactions).
Omeprazole (CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate): Coadministration
of omeprazole (40 mg once daily x 10 days) with oral voriconazole (400 mg Q12h x
1 day, then 200 mg Q12h x 9 days) increased the steady state Cmax
and AUCτ of voriconazole by an average of 15% (90% CI:
5%, 25%) and 40% (90% CI: 29%, 55%), respectively, in healthy subjects. No dosage
adjustment of voriconazole is recommended.
Coadministration of voriconazole (400 mg Q12h x 1 day, then 200 mg x 6 days) with
omeprazole (40 mg once daily x 7 days) to healthy subjects significantly increased
the steady state Cmax and AUCτ
of omeprazole an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3,
4.4), respectively, as compared to when omeprazole is given without voriconazole.
When initiating voriconazole in patients already receiving omeprazole doses of 40
mg or greater, it is recommended that the omeprazole dose be reduced by one-half
(see PRECAUTIONS – Drug Interactions).
The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also
be inhibited by voriconazole and may result in increased plasma concentrations of
these drugs.
Oral Contraceptives (CYP3A4 substrate; CYP2C19 inhibitor): Coadministration
of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 3 days) and oral
contraceptive (Ortho-Novum1/35® consisting of 35 mcg ethinyl
estradiol and 1 mg norethindrone, Q24h) to healthy female subjects at steady state
increased the Cmax and AUCτ
of ethinyl estradiol by an average of 36% (90% CI: 28%, 45%) and 61% (90% CI: 50%,
72%), respectively, and that of norethindrone by 15% (90% CI: 3%, 28%) and 53% (90%
CI: 44%, 63%), respectively in healthy subjects. Voriconazole Cmax
and AUCτ increased by an average of 14% (90% CI: 3%, 27%)
and 46% (90% CI: 32%, 61%), respectively. Monitoring for adverse events related
to oral contraceptives, in addition to those for voriconazole, is recommended during
coadministration (see PRECAUTIONS – Drug Interactions).
No significant pharmacokinetic interaction was seen and no dosage adjustment of
these drugs is recommended :
Indinavir (CYP3A4 inhibitor and substrate): Repeat dose administration
of indinavir (800 mg TID for 10 days) had no significant effect on voriconazole
Cmax and AUC following repeat dose administration (200
mg Q12h for 17 days) in healthy subjects.
Repeat dose administration of voriconazole (200 mg Q12h for 7 days) did not have
a significant effect on steady state Cmax and AUCτ
of indinavir following repeat dose administration (800 mg TID for 7 days) in healthy
subjects.
Other Two-Way Interactions Expected to be Significant Based on In Vitro and
In Vivo Findings:
Other HIV Protease Inhibitors (CYP3A4 substrates and inhibitors):
In vitro studies (human liver microsomes) suggest that voriconazole may inhibit
the metabolism of HIV protease inhibitors (e.g., saquinavir, amprenavir and nelfinavir).
In vitro studies (human liver microsomes) also show that the metabolism of
voriconazole may be inhibited by HIV protease inhibitors (e.g., saquinavir and amprenavir).
Patients should be frequently monitored for drug toxicity during the coadministration
of voriconazole and HIV protease inhibitors (see PRECAUTIONS – Drug Interactions).
Other Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (CYP3A4 substrates,
inhibitors or CYP450 inducers): In vitro studies (human liver microsomes)
show that the metabolism of voriconazole may be inhibited by a NNRTI (e.g., delavirdine).
The findings of a clinical voriconazole-efavirenz drug interaction study in healthy
male subjects suggest that the metabolism of voriconazole may be induced by a NNRTI.
This in vivo study also showed that voriconazole may inhibit the metabolism
of a NNRTI (see CLINICAL PHARMACOLOGY – Drug Interactions, PRECAUTIONS
– Drug Interactions). Patients should be frequently monitored for drug toxicity
during the coadministration of voriconazole and other NNRTIs (e.g., nevirapine and
delavirdine) (see PRECAUTIONS – Drug Interactions). Dose adjustments are required when voriconazole is co-administered with
efavirenz (see CLINICAL PHARMACOLOGY - Drug Interactions, PRECAUTIONS - Drug Interactions).
MICROBIOLOGY
Mechanism of Action
Voriconazole is a triazole antifungal agent. 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. Voriconazole
has been shown to be more selective for fungal cytochrome P-450 enzymes than for
various mammalian cytochrome P-450 enzyme systems.
Activity In Vitro
Voriconazole has been shown to be active against most strains of the following microorganisms,
both in vitro and in clinical infections.
Aspergillus fumigatus
Aspergillus flavus
Aspergillus niger
Aspergillus terreus
Candida albicans
Candida glabrata (In clinical studies, the voriconazole MIC90 was 4 μg/mL)*
Candida krusei
Candida parapsilosis
Candida tropicalis
Fusarium spp. including Fusarium solani
Scedosporium apiospermum
*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 (see Table 4).
The following data are available, but their clinical significance is unknown.
Voriconazole exhibits in vitro minimal inhibitory concentrations (MICs) of 1 μg/mL or less
against most (≥90%) isolates of the following microorganisms; however, the safety and
effectiveness of voriconazole in treating clinical infections due to these Candida species have not
been established in adequate and well-controlled clinical trials:
Candida lusitaniae
Candida guilliermondii
Susceptibility Testing Methods2,3
Aspergillus species and other filamentous fungi
No interpretive criteria have been established for Aspergillus species and other filamentous fungi.
Candida species
The interpretive standards for voriconazole against Candida species are applicable only to tests
performed using Clinical Laboratory and Standards Institute (CLSI) microbroth dilution
reference method M27 for MIC read at 48 hours or disk diffusion reference method M44 for zone diameter read at 24 hours.2,3
Broth Microdilution Techniques: Quantitative methods are used to determine antifungal
minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility
of Candida spp. to antifungal agents. MICs should be determined using a standardized
procedure at 48 hours.2 Standardized procedures are based on a microdilution method (broth) with standardized inoculum concentrations and standardized concentrations of voriconazole powder. The MIC values should be interpreted according to the criteria provided in Table 4.
Diffusion Techniques: Qualitative methods that require measurement of zone diameters also
provide reproducible estimates of the susceptibility of Candida spp. to an antifungal agent. One
such standardized procedure requires the use of standardized inoculum concentrations.3 This
procedure uses paper disks impregnated with 1 μ g of voriconazole to test the susceptibility of
yeasts to voriconazole at 24 hours. Disk diffusion interpretive criteria are also provided in Table 4.
Table 4: Susceptibility Interpretive Criteria for Voriconazole2,3
NOTE: Shown are the breakpoints (μ g/mL) for voriconazole against Candida species.
The susceptible category implies that isolates are inhibited by the usually achievable
concentrations of antifungal agent tested when the recommended dosage is used for the site of
infection. The intermediate category implies that an infection due to the isolate may be
appropriately treated in body sites where the drugs are physiologically concentrated or when a
high dosage of drug is used. The resistant category implies that isolates are not inhibited by the
usually achievable concentrations of the agent with normal dosage schedules and clinical efficacy of the agent against the isolate has not been reliably shown in treatment studies.
The susceptible category implies that isolates are inhibited by the usually achievable
concentrations of antifungal agent tested when the recommended dosage is used for the site of
infection. The intermediate category implies that an infection due to the isolate may be
appropriately treated in body sites where the drugs are physiologically concentrated or when a
high dosage of drug is used. The resistant category implies that isolates are not inhibited by the
usually achievable concentrations of the agent with normal dosage schedules and clinical efficacy of the agent against the isolate has not been reliably shown in treatment studies.
Quality Control
Standardized susceptibility test procedures require the use of quality control organisms to control
the technical aspects of the test procedures. Standard voriconazole powder and 1 μ g disks should provide the following range of values noted in Table 5.
NOTE: Quality control microorganisms are specific strains of organisms with intrinsic
biological properties relating to resistance mechanisms and their genetic expression within fungi;
the specific strains used for microbiological control are not clinically significant.
Table 5
Acceptable Quality Control Ranges for Voriconazole to be used in Validation of
Susceptibility Test Results
* Quality control ranges have not been established for this strain/antifungal agent combination due to their extensive
interlaboratory variation during initial quality control studies.
ATCC is a registered trademark of the American Type Culture Collection.
Activity In Vivo
Voriconazole was active in normal and/or immunocompromised guinea pigs with systemic
and/or pulmonary infections due to A. fumigatus (including an isolate with
reduced susceptibility to itraconazole) or Candida species [C. albicans
(including an isolate with reduced susceptibility to fluconazole), C. krusei
and C. glabrata] in which the endpoints were prolonged survival of infected
animals and/or reduction of mycological burden from target organs. In one experiment,
voriconazole exhibited activity against Scedosporium apiospermum infections
in immune competent guinea pigs.
Drug Resistance
Voriconazole drug resistance development has not been adequately studied in vitro
against Candida, Aspergillus, Scedosporium and Fusarium species. 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.
References
- Clinical Laboratory Standards Institute. Reference method for broth dilution antifungal
susceptibility testing of conidium-forming filamentous fungi. Approved Standard M38-P.
Clinical Laboratory Standards Institute, Villanova, Pa.
- Clinical Laboratory Standards Institute. Reference method for broth dilution antifungal
susceptibility testing of yeasts. Approved Standard M27-A. Clinical Laboratory Standards
Institute, Villanova, Pa.
-
Clinical Laboratory Standards Institute. Method for antifungal disk diffusion susceptibility
testing of yeasts. Approved guideline M44-A. Clinical Laboratory Standards Institute,
Villanova, Pa.