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Investigation of the Potential Relationships Between Plasma Voriconazole Concentrations and Visual
Adverse Events or Liver Function Test Abnormalities
Keith Tan, Nigel Brayshaw, Konrad Tomaszewski, Peter Troke and Nolan Wood
J. Clin. Pharmacol. 2006; 46; 235
DOI: 10.1177/0091270005283837

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TAN ET AL
10.1177/0091270005283837
PLASMA
ADVERSE VORICONAZOLE
EVENTS CONCENTRATION AND ADVERSE EVENTS
Investigation of the Potential Relationships
Between Plasma Voriconazole Concentrations
and Visual Adverse Events or
Liver Function Test Abnormalities
Keith Tan, PhD, Nigel Brayshaw, MSc, Konrad Tomaszewski, PhD,
Peter Troke, PhD, and Nolan Wood, PhD
This study investigated the relationship between plasma
voriconazole concentrations (pVC) and risk of visual adverse
events (VAEs) or liver function test (LFT) abnormalities using
longitudinal logistic regression. Seven-day mean pVC were
calculated from 2925 plasma samples (1053 patients); in each
7-day period, the presence or absence of VAEs/abnormal
LFTs was analyzed as a binary outcome variable. There was a
relationship between pVC and risk of VAE (P = .011) and a
weaker, but statistically significant, association with risk of
aspartate transaminase (AST), alkaline phosphatase (ALP),
or bilirubin but not alanine transaminase (ALT) abnormali-
V oriconazole is an extended-spectrum, triazole anti-
fungal agent that is approved, depending on the
country, for the primary treatment of invasive asper-
gillosis and as therapy for Scedosporium species and
Fusarium species infections, as well as infections
caused by Candida.1-3 It is active in vitro against Can-
dida species, Aspergillus species, and other fungal gen-
era including fluconazole-, itraconazole-, and ampho-
tericin B–resistant isolates. Voriconazole is available in
both intravenous and oral (tablet and oral suspension)
formulations.2,3
In clinical studies, visual disturbances were the
most commonly reported treatment-related adverse
From Clinical Pharmacology (Dr Tan, Dr Wood), Development Operations
(Mr Brayshaw), Regulatory Affairs (Dr Tomaszewski), and Clinical R&D (Dr
Troke), Pfizer Global Research and Development, Sandwich, Kent, United
Kingdom. Submitted for publication June 23, 2005; revised version ac-
cepted October 16, 2005. Online study sites can be accessed from http://
jcp.sagepub.com/cgi/content/full/46/2/235/DC1/. Address for reprints:
Keith Tan, Clinical R&D (IPC 096), Pfizer Global Research and Develop-
ment, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom.
DOI: 10.1177/0091270005283837
J Clin Pharmacol 2006;46:235-243
ADVERSE EVENTS
ties. The odds ratios of LFT abnormalities per 1 µg/mL pVC
increase ranged from 1.07 to 1.17. Maximum weekly occur-
rences were 10%, 8%, 5%, and 14% for AST, ALT, ALP, and
bilirubin abnormalities, respectively. Receiver-operating
characteristic curve analysis indicates that individual pVC
cannot be used to predict subsequent LFT abnormalities.
Keywords: Voriconazole; visual adverse event, liver function
test, plasma concentration
Journal of Clinical Pharmacology, 2006;46:235-243
©2006 the American College of Clinical Pharmacology
event with voriconazole.4-7 These events occurred with
an overall frequency of approximately 30% in patients
but were transient, rarely required drug discontinua-
tion, and were fully reversible.1,4-10 A mechanistic
study using electroretinograms in healthy volunteers
dosed at 300 mg twice daily for a period of 28 days con-
firmed that the effect of voriconazole on visual func-
tion is fully reversible.10,11 In addition, a recently com-
pleted study in which patients received voriconazole
200 mg twice daily for at least 6 months revealed no ev-
idence of an effect of voriconazole on long-term visual
function.12
In addition to visual disturbances, there were re-
ports of liver function test (LFT) abnormalities associ-
ated with voriconazole use. These were usually mild to
moderate in intensity, and most patients did not re-
quire treatment discontinuation.4-8,13 Using the defini-
tions summarized in Table I,9 the overall incidence of
clinically significant transaminase abnormalities in
patients participating in voriconazole therapeutic
studies was 12.4% (Pfizer; data on file).
Increases in LFT abnormalities with voriconazole
may be associated with dose, as demonstrated in a
235
 TAN ET AL
Table I Criteria for Clinically Significant
Abnormality for Liver Function Tests (LFTs)
LFT Measure Baseline Test Result
ALT, AST, or ALP <2 times ULN ≥5 times baseline
≥2 times ULN and
<5 times ULN ≥3 times baseline
≥5 times ULN and
<10 times ULN ≥2 times baseline
≥10 times ULN ≥1.5 times baseline
Bilirubin ≥3 mg/dL >Baseline
phase 1 healthy volunteer dose-escalation study13 and
a dose escalation, safety, and pharmacokinetic (PK)
study in patients at risk of fungal infection.7 In the
healthy volunteer study, there were no LFT abnormali-
ties in 14 subjects who received voriconazole at doses
of 6 mg/kg every 12 hours intravenously on day 1, fol-
lowed by 3 mg/kg every 12 hours intravenously for 6
days, followed by 200 mg every 12 hours orally for 7
days. However, when the same group received vori-
conazole at doses of 6 mg/kg every 12 hours intrave-
nously on day 1 followed by 5 mg/kg every 12 hours in-
travenously for 6 days followed by 400 mg every 12
hours orally for 7 days, 5 of 14 subjects had either
aspartate transaminase (AST) or alanine transaminase
(ALT) values above the upper limit of normal
(ULN).13,14 In the patients at risk of fungal infection,
there were no LFT abnormalities in 9 patients who re-
ceived oral voriconazole at doses of 200 mg every 12
hours for 14 days. In a separate group dosed at 300 mg
every 12 hours orally, 1 of 9 patients had an AST more
than 3 times the ULN (146 IU/L) on the last day of treat-
ment (day 14), which returned to normal range (9-34
IU/L) by day 27.7 In clinical trials comparing voricon-
azole with conventional or liposomal amphotericin B,
the rates of LFT abnormalities were comparable be-
tween the voriconazole and liposomal or conventional
amphotericin B groups.5,8,9,14
In a study to examine the efficacy and safety of vori-
conazole in the treatment of acute invasive aspergillo-
sis, Denning et al15 reported that 6 of 22 patients who
developed abnormal liver function or liver failure had
plasma voriconazole concentrations higher than 6 µg/
mL. Furthermore, a review of hepatic laboratory abnor-
malities reported in clinical trials of voriconazole by
Potoski and Brown16 concluded that although it is not
certain, there may be an association between abnormal
liver function and plasma voriconazole concen-
trations higher than 6 µg/mL. The authors felt that dose-
modification guidelines needed to be developed based
236 • J Clin Pharmacol 2006;46:235-243
on plasma voriconazole concentrations. In contrast,
Lutsar et al17 presented data that indicated that plasma
voriconazole concentrations were not predictive of ab-
normal LFT findings or treatment outcomes.
Given that the PK of voriconazole is nonlinear with
respect to dose13 and that there is wide interindividual
variability in plasma concentrations at a given dose,18,19
it is important to understand any potential relationship
between voriconazole plasma concentrations and
safety. This retrospective analysis was therefore carried
out to investigate the relationship between plasma
voriconazole concentrations and the risk of visual ad-
verse events (VAEs) or LFT abnormalities in a large co-
hort of patients who were included in the phase 2 and 3
clinical trials.
METHODS
Study Design
Safety and PK data from 10 phase 2 or 3 voriconazole
therapeutic trials were analyzed retrospectively. Each
clinical study protocol was approved prior to the start
by independent ethics review committees whose con-
stitutions were appropriate for the countries in which
the studies were performed (for specific sites see the
online appendix at http://jcp.sagepub.com/cgi/con-
tent/full/46/2/235/DC1/). A total of 2925 weekly (7-
day mean) plasma voriconazole concentrations were
calculated using PK data from 1053 patients. This pop-
ulation included all patients from whom at least 1
plasma voriconazole concentration was obtained. The
presence or absence of VAEs and time to onset from
start of treatment were examined. The LFT outcome
variables were recorded for each 7-day interval as the
presence or absence of ALT, AST, alkaline phosphatase
(ALP), or bilirubin abnormalities and were classified
using the criteria summarized in Table I. These criteria
are based on LFT values at the start of treatment, since
some patients were recruited into studies with LFT val-
ues greater than the ULN.
Demography, Etiology, and
Underlying Disease
The patient population consisted of 682 males (64.8%)
and 371 females (35.2%). Most (81.8%) of the patients
were white; the remainder were black (9.8%) and
Asian/other (8.5%). Ages ranged from 11 to 85 years,
with a mean of 44 years.
Patients were pooled from 10 therapeutic clinical
trials including empirical therapy and treatment of in-
fections such as aspergillosis, esophageal candidiasis,
 PLASMA VORICONAZOLE CONCENTRATION AND ADVERSE EVENTS
candidemia, scedosporiosis, and fusariosis. Most pa-
tients had serious underlying conditions, including
hematologic malignancy, allogeneic or autologous
hematopoietic cell transplantation, solid organ trans-
plantation, or AIDS, and almost half were neutropenic
(<500 cells/mm3).
Pharmacokinetics
Plasma voriconazole concentrations were measured by
a validated high-performance liquid chromatography
assay.20 The lower limit of quantification was set at 0.1
µg/mL; concentrations below that limit were recorded
as 0 in the analyses.
The raw PK data were summarized as weekly mean
plasma voriconazole concentrations. While PK sam-
ples may have been taken over any part of the dosing
interval, intraindividual variability in plasma voricon-
azole concentrations within the dosing interval and be-
tween doses was low compared with interindividual
variability. Therefore, mean plasma concentrations
were considered appropriate for the characterization of
differences in exposure between individuals.
The weekly mean plasma concentrations were used
as the PK explanatory variable in the PK/pharmaco-
dynamic (PD) modeling. The number of weekly mean
concentrations per patient ranged from 1 to 13, and the
range of weekly concentrations was 0 to 20.4 µg/mL
with a mean of 3.2 µg/mL.
Visual Adverse Events
The presence or absence of treatment-emergent visual
adverse VAEs was analyzed as a binomial outcome
variable using adverse event data recorded during the
course of the studies. The term visual adverse event
represents the composite of reports of visual distur-
bances captured during voriconazole treatment. The
specific events captured included enhanced/altered
visual perception, blurred vision, changes in color vi-
sion, photophobia, and other. The “other” category en-
compassed events that could not easily be catego-
rized, such as “dots” and “scotomata” or imprecise
terms such as visual disturbance that could not be
categorized.
LFT Analyses
ALT, AST, ALP, and bilirubin concentrations were
measured at baseline and monitored at predetermined
time points during voriconazole administration in the
various clinical studies. A binary variable was used to
indicate an LFT abnormality for each 7-day interval.
ADVERSE EVENTS
The criteria used to define abnormal LFT values are
summarized in Table I.
Exploratory Analyses of the PK/PD
Relationship and Receiver-Operating
Characteristic Curves
The overall percentage occurrences of VAEs or ALT,
AST, ALP, or bilirubin abnormalities were plotted
against plasma voriconazole concentration categories.
Receiver-operating characteristic (ROC) curves were
also plotted to explore the trade-off between the sensi-
tivity and specificity of predicting LFT abnormalities
from preceding plasma voriconazole concentrations.
ROC curves examine the relationship between the
probability of a true-positive test (sensitivity) against
that of a false-positive test (1 – specificity) for chosen
plasma concentration cut points. In addition, the posi-
tive and negative predictive values of each test were
calculated.21,22
Modeling the
PK/PD Relationship
The PK/PD relationships between mean plasma
voriconazole concentrations and VAEs or LFTs were
investigated by longitudinal logistic regression using
the generalized estimating equations approach.23 The
predicted probability of an event, without covariate ad-
justment, was plotted with respect to plasma voricon-
azole concentration. The corresponding 95% confi-
dence intervals were also presented to indicate the
degree of uncertainty of the estimated probability of an
event for a given plasma voriconazole concentration.
To investigate potential threshold effects, the continu-
ous plasma concentration term was replaced by 10
plasma concentration categories (ie, 0 to <1, 1 to <2, 2 to
<3, . . . , 8 to <9, and 9+ µg/mL).
Covariates
The following factors were identified a priori as poten-
tial covariates to be explored: study, age, gender,
weight, race, indication, primary underlying condi-
tion, hematologic risk factors, and study medication
use. For each analysis, covariates were selected for the
PK/PD model by the method of forward selection. The
potential for a differing PK/PD relationship per
covariate was also explored by fitting interaction terms
in the model. Each PK/PD model was fitted with and
without covariates. However, for all analyses, the un-
derlying PK/PD relationship was similar in each case.
237
 TAN ET AL

Figure 1. Plasma voriconazole concentrations and visual adverse events. The percentage weekly occurrence shown is the number of events ob-
served in weekly time periods over the total number of weekly time periods (numbers shown above each symbol) for each plasma voriconazole
concentration category.

RESULTS .011) and showed that the overall incidence of VAEs

For each analysis, the PK/PD relationship did not differ
according to covariates; that is, no significant plasma
voriconazole concentration-by-covariate interactions
were found.
Visual Adverse Events
Inspection of the weekly plasma concentration data
from patients in phase 2 and 3 studies suggests that
those patients who reported a VAE had higher voricon-
azole plasma concentrations. During the first week of
voriconazole administration, the median plasma
voriconazole concentration for patients experiencing a
VAE was 3.52 µg/mL, and for those not experiencing a
VAE, it was 2.72 µg/mL. This pattern was similar dur-
ing the second week of voriconazole administration
and remained evident throughout the duration of the
treatment.
The longitudinal logistic regression analysis re-
vealed a significant relationship between plasma
voriconazole concentration and the odds of a VAE (P =
varied between studies. The model predicted a 4.7%
increase in the odds of a VAE for every 1 µg/mL in-
crease in plasma voriconazole concentration. The pre-
dicted probability of a VAE increased from 18% to 31%
for a change in plasma voriconazole concentration
from 0 to 9 µg/mL (Figure 1). Model predictions greater
than 9 µg/mL were considered unreliable due to wide
confidence intervals.
Liver Function Tests
ALT, AST, ALP, and bilirubin abnormalities occurred
in <10% of patients, with the exception of the >9 µg/
mL category for bilirubin (Figures 2A-5A). For ALT, the
slope of the model estimate is shallow and the confi-
dence intervals are wide, indicating lack of evidence
for a relationship between plasma voriconazole con-
centration and ALT abnormalities (Figure 2B). For
AST, ALP, and bilirubin, the predicted probabilities of
an abnormality increased from approximately 3% to
8%, 1% to 3%, and 3% to 10%, respectively, for a
change in plasma voriconazole concentration from 0 to

238 • J Clin Pharmacol 2006;46:235-243

 PLASMA VORICONAZOLE CONCENTRATION AND ADVERSE EVENTS

Figure 2. Plasma voriconazole concentrations and risk of ALT abnormalities. The percentage weekly occurrence shown is the number of
events observed in weekly time periods over the total number of weekly time periods (numbers shown above each symbol) for each plasma
voriconazole concentration category.

Figure 3. Plasma voriconazole concentrations and risk of AST abnormalities. The percentage weekly occurrence shown is the number of events
observed in weekly time periods over the total number of weekly time periods (numbers shown above each symbol) for each plasma voriconazole
concentration category.

9 µg/mL (Figures 3B-5B). Model predictions greater
than 9 µg/mL were considered unreliable due to wide
confidence intervals. There is no apparent threshold
plasma concentration above which the odds of an
abnormality were increased for any of the LFTs
analyzed.
Longitudinal logistic regression analysis revealed a
statistically significant relationship (P < .001) between
plasma voriconazole concentration and the odds of an
AST, ALP, and bilirubin abnormality. The model pre-
dicted a 13.1%, 16.5%, and 17.2% increase in the odds
of an AST, ALP, and bilirubin abnormality, respec-

ADVERSE EVENTS 239

 TAN ET AL

Figure 4. Plasma voriconazole concentrations and risk of ALP abnormalities. The percentage weekly occurrence shown is the number of
events observed in weekly time periods over the total number of weekly time periods (numbers shown above each symbol) for each plasma
voriconazole concentration category.

Figure 5. Plasma voriconazole concentrations and risk of bilirubin abnormalities. The percentage weekly occurrence shown is the number of
events observed in weekly time periods over the total number of weekly time periods (numbers shown above each symbol) for each plasma
voriconazole concentration category.

tively, for every 1 µg/mL increase in plasma voricon-
azole concentration (Table II). There was no significant
relationship between plasma voriconazole and the
odds of an ALT abnormality (P = .171). The model pre-
dicted a 7.4% increase in the odds of an ALT abnormal-
ity for every 1 µg/mL increase in plasma voriconazole
concentration (Table II).
A different set of covariates was found to be signifi-
cant for each LFT analysis: ALT abnormalities were
more strongly associated with the risk factor “bone

240 • J Clin Pharmacol 2006;46:235-243

 PLASMA VORICONAZOLE CONCENTRATION AND ADVERSE EVENTS
Table II Key Statistics From Longitudinal
Logistic Regression (Odds Ratios per 1 µg/mL
After Adjusting for Covariates)
Lower Upper
Odds 95% 95%
Abnormality/Event Ratio Bound Bound
ALT 1.07 0.97 1.19
AST 1.13 1.06 1.20
ALP 1.16 1.08 1.25
Bilirubin 1.17 1.08 1.27
marrow transplant” compared with no known risk fac-
tor (odds ratio [OR] = 3.4) and the underlying condition
“other immunosuppression” compared with “cancer”
(OR = 6.5). The odds of an AST abnormality varied
across clinical studies, age, and gender. The risk of a
bilirubin abnormality varied according to race, under-
lying disease, and hematologic risk factor. The odds of
a bilirubin abnormality were highest in “bone marrow
transplant” and “neutropenic” patients compared with
no known hematologic risk factor (OR = 7.5 and 5.1, re-
spectively). The risk of an ALP abnormality varied
according to gender (OR = 3.0 M/F).
ROC Curve Analysis
The ROC curve for AST abnormalities for each of the
voriconazole plasma concentration cut points (0.5 to
10 µg/mL) closely follows the 45° line of identity or no
discrimination (Figure 6). This indicates that for all po-
tential plasma concentration cut points, the proportion
of abnormalities correctly predicted by the test (sensi-
tivity) were similar to the proportion of wrong predic-
tions of abnormality (1 – specificity). The results for
ALT, ALP, and bilirubin were similar (data not shown).
Positive predictive values for AST, ALT, ALP, and bili-
rubin at the 10 µg/mL cut point were approximately
12%, 9%, 7%, and 16%, respectively.
DISCUSSION
Investigations of PK/PD relationships in phase 2 and 3
populations are challenging when variability in both
PK and PD is potentially confounded by multiple fac-
tors such as differences in demographics, underlying
disease, pathogens, and concomitant medications.
However, this population is the most relevant for un-
derstanding PK/PD relationships with respect to
dosing strategy.
Although none of the clinical efficacy studies were
specifically designed for PK/PD evaluation, this retro-
ADVERSE EVENTS
Figure 6. ROC curve for predicting AST abnormalities from plasma
voriconazole concentrations.
spective analysis was carried out to determine whether
there was a relationship between plasma voriconazole
concentration and the risk of a VAE or an LFT abnor-
mality in voriconazole-treated patients.
Visual events were the most common voriconazole-
related adverse events in patients and volunteers, and
their frequency increased with increasing plasma vori-
conazole concentrations. In healthy volunteers, both
the maximum plasma concentration (Cmax) and the area
under the plasma concentration-time curve (AUC) were
positively associated with VAEs (data not shown). It
was not possible to use the data from this analysis to ex-
amine relationships between VAEs and Cmax or AUC in
patients. However, analysis of mean plasma concentra-
tion data in patients was consistent with the data in
healthy volunteers, suggesting that VAEs were more
likely in patients with higher mean plasma voricona-
zole concentrations.
In the LFT analyses, for most weekly periods over
the interval studied, the median plasma voriconazole
concentrations were higher in patients with ALT, ALP,
and bilirubin abnormalities than in patients without
abnormalities. However, over the plasma concentra-
tion bands summarized, the weekly occurrence of LFT
abnormalities was low, with maximum occurrences of
approximately 10%, 8%, 5%, and 14% for AST, ALT,
ALP, and bilirubin, respectively.
Potoski and Brown16 proposed therapeutic drug
monitoring of patients treated with voriconazole to re-
duce the incidence of LFT abnormalities. However, the
overall incidence of LFT elevations for voriconazole-
treated patients in the comparative studies was similar
to those in the AmBisome or amphotericin B deoxy-
cholate arms8,9 and to those recorded for other agents
241
 TAN ET AL
and comparable patient groups.24 In response, Lutsar
et al17 considered that therapeutic drug monitoring
would be unlikely to add any value over clinical judg-
ment and diligent monitoring of LFTs.
Therapeutic drug monitoring can be a useful clinical
approach with drugs such as cyclosporine, in which
narrow plasma concentration thresholds differentiate
between therapeutic and potentially nephrotoxic
doses. Using ROC curve analysis, it is possible to deter-
mine threshold plasma concentrations of cyclosporine
that optimize efficacy and minimize nephrotoxicity.25
In the ROC curve for cyclosporine and nephrotoxicity,
there are positive and significant deviations from the
line of identity, indicating that cyclosporine concentra-
tion can be used to detect a high proportion of cases of
potential nephrotoxicity, with a few false positives.
In contrast, the evidence presented here suggests that
the absolute risk of an LFT abnormality in voriconazole-
treated patients is low. There was no statistically sig-
nificant relationship between plasma voriconazole
concentrations and ALT abnormalities, whereas statis-
tically significant, but weak, associations were identi-
fied between plasma voriconazole concentrations and
AST, ALP, and bilirubin abnormalities. Furthermore,
unlike cyclosporine,21 ROC curve analysis indicated
that plasma voriconazole concentrations cannot be
used to discriminate between true-positive and false-
positive LFT abnormalities using cut points of vori-
conazole plasma concentrations from 0.5 to 10 µg/mL.
Therefore, individual plasma voriconazole concentra-
tions cannot be regarded as a good predictor for LFT
abnormalities.
There is also little value in measuring plasma vori-
conazole concentrations in the absence of an abnormal
LFT. For example, the model predicts a probability of
an AST abnormality of 7%, even when the plasma vori-
conazole concentration is as high as 10 µg/mL. The
ROC analysis shows that discontinuing or altering ther-
apy solely because the plasma voriconazole concentra-
tion was 10 µg/mL would be unnecessary in 88% of
cases since this strategy was associated with a posi-
tive predictive value of only 12%. Hence, routine LFT
measurement would provide more valuable clinical
information than monitoring plasma voriconazole
concentrations.
In conclusion, the relationships between plasma
voriconazole concentrations and VAE and LFT abnor-
malities have been explored quantitatively. ROC analy-
sis indicated that therapeutic drug monitoring is un-
likely to add any value over routine LFT monitoring
and clinical judgment in guiding dose adjustment in
patients treated with voriconazole.
242 • J Clin Pharmacol 2006;46:235-243
This work was carried out with the financial support of Pfizer Inc.
The authors acknowledge Michael Oakes for his contribution to the
analyses of these studies.
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