Pharmacokinetics, safety, and tolerability of voriconazole in immunocompromised children.
ABSTRACT The pharmacokinetics of voriconazole in children receiving 4 mg/kg intravenously (i.v.) demonstrate substantially lower plasma exposures (as defined by area under the concentration-time curve [AUC]) than those in adults receiving the same therapeutic dosage. These differences in pharmacokinetics between children and adults limit accurate prediction of pediatric voriconazole exposure based on adult dosages. We therefore studied the pharmacokinetics and tolerability of higher dosages of an i.v.-to-oral regimen of voriconazole in immunocompromised children aged 2 to <12 years in two dosage cohorts for the prevention of invasive fungal infections. The first cohort received 4 mg/kg i.v. every 12 h (q12h), then 6 mg/kg i.v. q12h, and then 4 mg/kg orally (p.o.) q12h; the second received 6 mg/kg i.v. q12h, then 8 mg/kg i.v. q12h, and then 6 mg/kg p.o. q12h. The mean values for the AUC over the dosing interval (AUCτ) for 4 mg/kg and 6 mg/kg i.v. in cohort 1 were 11,827 and 22,914 ng.h/ml, respectively, whereas the mean AUCτ values for 6 mg/kg and 8 mg/kg i.v. in cohort 2 were 17,249 and 29,776 ng.h/ml, respectively. High interpatient variability was observed. The bioavailability of the oral formulation in children was approximately 65%. The safety profiles were similar in the two cohorts and age groups. The most common treatment-related adverse event was increased gamma glutamyl transpeptidase levels. There was no correlation between adverse events and voriconazole exposure. In summary, voriconazole was tolerated to a similar degree regardless of dosage and age; the mean plasma AUCτ for 8 mg/kg i.v. in children approached that for 4 mg/kg i.v. in adults, thus representing a rationally selected dosage for the pediatric population.
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ABSTRACT: Our objective was to describe the association between voriconazole concentrations and CYP2C19 diplotypes in pediatric cancer patients, including children homozygous for the CYP2C19*17 gain-of-function allele.Pharmacogenomics 06/2014; 15(8):1065-78. · 3.43 Impact Factor
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ABSTRACT: Invasive fungal disease (IFD) remains life threatening in premature infants and immunocompromised children despite the recent development of new antifungal agents. Optimal dosing of antifungals is one of the few factors clinicians can control to improve outcomes of IFD. However, dosing in children cannot be extrapolated from adult data because IFD pathophysiology, immune response, and drug disposition differ from adults. We critically examined the literature on pharmacokinetics (PK) and pharmacodynamics (PD) of antifungal agents and highlight recent developments in treating pediatric IFD. To match adult exposure in pediatric patients, dosing adjustment is necessary for almost all antifungals. In young infants, the maturation of renal and metabolic functions occurs rapidly and can significantly influence drug exposure. Fluconazole clearance doubles from birth to 28 days of life and, beyond the neonatal period, agents such as fluconazole, voriconazole, and micafungin require higher dosing than in adults because of faster clearance in children. As a result, dosing recommendations are specific to bracketed ranges of age. PD principles of antifungals mostly rely on in vitro and in vivo models but very few PD studies specifically address IFD in children. The exposure-response relationship may differ in younger children compared with adults, especially in infants with invasive candidiasis who are at higher risk of disseminated disease and meningoencephalitis, and by extension severe neurodevelopmental impairment. Micafungin is the only antifungal agent for which a specific target of exposure was proposed based on a neonatal hematogenous Candida meningoencephalitis animal model. In this review, we found that pediatric data on drug disposition of newer triazoles and echinocandins are lacking, dosing of older antifungals such as fluconazole and amphotericin B products still need optimization in young infants, and that target PK/PD indices need to be clinically validated for almost all antifungals in children. A better understanding of age-specific PK and PD of new antifungals in infants and children will help improve clinical outcomes of IFD by informing dosing and identifying future research areas.Drugs 05/2014; · 4.13 Impact Factor
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ABSTRACT: We investigated the incidence of phototoxic skin reactions in pediatric BMT recipients treated with voriconazole. Nine out of 40 patients (22.5%), all Caucasian, developed skin lesions in sun-exposed distributions. Dermatologic findings included sunburn-like erythema, pseudo-porphyria, linear papulovesicular lesions, severe erosive cheilitis, dermatoheliosis and lentigines. Patients were treated with sun avoidance, high-potency sunscreens, and topical steroids with significant improvement in all cases. Prolonged voriconazole use requires close monitoring for chronic skin toxicities. Long-term risks including the risk of skin cancer need to be investigated. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.Pediatric Blood & Cancer 03/2014; · 2.35 Impact Factor
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Oct. 2010, p. 4116–4123
Copyright © 2010, American Society for Microbiology. All Rights Reserved.
Vol. 54, No. 10
Pharmacokinetics, Safety, and Tolerability of Voriconazole
in Immunocompromised Children?
Thomas J. Walsh,1,2* Timothy Driscoll,3Peter A. Milligan,4Nolan D. Wood,5Haran Schlamm,4,5
Andreas H. Groll,6Hasan Jafri,7Antonio C. Arrieta,8Nigel J. Klein,9and Irja Lutsar4,10†
Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland1; Weill Cornell Medical College of Cornell University,
New York, New York2; Department of Pediatrics and Duke Clinical Research Institute, Duke University, Durham,
North Carolina3; Pfizer Ltd., Sandwich, Kent, United Kingdom4; Pfizer Inc., New York, New York5;
Wilhelms-University, Mu ¨nster, Germany6; Simmons Cancer Center at University of Texas
Southwestern Medical Center, Dallas, Texas7; Children’s Hospital of Orange County,
Orange, California8; Institute of Child Health, University College London, London,
United Kingdom9; and Tartu University, Institute of
Medical Microbiology, Tartu, Estonia10
Received 1 July 2010/Accepted 17 July 2010
The pharmacokinetics of voriconazole in children receiving 4 mg/kg intravenously (i.v.) demonstrate sub-
stantially lower plasma exposures (as defined by area under the concentration-time curve [AUC]) than those
in adults receiving the same therapeutic dosage. These differences in pharmacokinetics between children and
adults limit accurate prediction of pediatric voriconazole exposure based on adult dosages. We therefore
studied the pharmacokinetics and tolerability of higher dosages of an i.v.-to-oral regimen of voriconazole in
immunocompromised children aged 2 to <12 years in two dosage cohorts for the prevention of invasive fungal
infections. The first cohort received 4 mg/kg i.v. every 12 h (q12h), then 6 mg/kg i.v. q12h, and then 4 mg/kg
orally (p.o.) q12h; the second received 6 mg/kg i.v. q12h, then 8 mg/kg i.v. q12h, and then 6 mg/kg p.o. q12h.
The mean values for the AUC over the dosing interval (AUC?) for 4 mg/kg and 6 mg/kg i.v. in cohort 1 were
11,827 and 22,914 ng ? h/ml, respectively, whereas the mean AUC? values for 6 mg/kg and 8 mg/kg i.v. in cohort
2 were 17,249 and 29,776 ng ? h/ml, respectively. High interpatient variability was observed. The bioavailability
of the oral formulation in children was approximately 65%. The safety profiles were similar in the two cohorts
and age groups. The most common treatment-related adverse event was increased gamma glutamyl transpep-
tidase levels. There was no correlation between adverse events and voriconazole exposure. In summary,
voriconazole was tolerated to a similar degree regardless of dosage and age; the mean plasma AUC? for 8 mg/kg
i.v. in children approached that for 4 mg/kg i.v. in adults, thus representing a rationally selected dosage for the
Invasive fungal infections cause severe morbidity and mor-
tality in immunocompromised children, particularly those with
hematological malignancies and those undergoing hematopoi-
etic stem cell transplantation (HSCT) (3, 8, 11, 19, 21, 27, 28).
Voriconazole is a broad-spectrum antifungal triazole with in
vitro and in vivo activity against yeasts and filamentous fungi (2,
5). Voriconazole is approved for adults for primary treatment
of invasive aspergillosis, esophageal candidiasis, and candi-
demia in nonneutropenic patients. It is also approved for the
treatment of serious, refractory infections caused by Scedospo-
rium and Fusarium species (16, 25). Voriconazole is more
effective than deoxycholate amphotericin B in treatment of
invasive aspergillosis in adults, most of whom suffered from
invasive pulmonary aspergillosis (9). In addition, voricon-
azole has been used successfully to treat aspergillosis of the
central nervous system and bone (14, 20).
Several case series and single case reports have described
the safety and efficacy of voriconazole in pediatric oncology
patients and other immunocompromised children with invasive
mycoses (10, 24, 26). Voriconazole also has been used to treat
Aspergillus airway disease in pediatric patients with cystic fi-
brosis (10). However, considerably less is known about the
pharmacokinetics of this antifungal agent in children than
about those in adults.
Current studies indicate that there are major differences
between the pharmacokinetics of voriconazole in children and
those in adults. The first systematic study of the safety, toler-
ability, and pharmacokinetics of voriconazole in pediatric pa-
tients demonstrated linear plasma pharmacokinetics in pa-
tients receiving intravenous (i.v.) voriconazole at dosages of 3
mg/kg every 12 h (q12h) or 4 mg/kg q12h (24). By comparison,
voriconazole in adults displays nonlinear Michaelis-Menten
plasma pharmacokinetics following similar dosages (17, 18).
These differences in pharmacokinetics between children and
adults limit accurate prediction of pediatric voriconazole ex-
posure (as defined by area under the concentration-time curve
[AUC]) based on adult dosages. Indeed, pharmacokinetic
modeling studies demonstrated that the AUC was approxi-
mately 3-fold lower in children receiving 4 mg/kg of voricon-
azole q12h than in adults receiving the same dosage.
* Corresponding author. Mailing address: Transplantation-Oncol-
ogy Infectious Diseases Program, Weill Cornell Medical College of
Cornell University, 1300 York Ave., Rm. A-421, New York, NY 10065.
Phone: (212) 746-6320. Fax: (212) 746-8852. E-mail: thw2003@med
† Present address: Institute of Microbiology, University of Tartu,
?Published ahead of print on 26 July 2010.
Therefore, in order to approximate the plasma exposure
achieved in adults, we studied the safety, tolerability, and
plasma pharmacokinetics of voriconazole in pediatric patients
receiving dosages of 4, 6, and 8 mg/kg i.v. q12h. We also
examined the plasma pharmacokinetics of the oral suspension
of voriconazole at 4 and 6 mg/kg q12h.
MATERIALS AND METHODS
Study design. This study was designed and conducted as an open-label, mul-
ticenter study of immunocompromised pediatric patients to whom voriconazole
was administered for prevention of invasive fungal infections. The study was
conducted in two consecutive cohorts, each consisting of a minimum of 18
evaluable patients. The study design, dosages, and cohorts are summarized in
Table 1. Each age group included 9 ? 1 evaluable patients aged 2 to ?6 years
and 9 ? 1 patients aged 6 to ?12 years. The first 18 patients were enrolled in
cohort 1, in which the following dosing regimen was used: on day 1, a loading
dose of 6 mg/kg q12h i.v.; on days 2 to 4, 4 mg/kg q12h i.v.; on days 5 to 8, 6 mg/kg
q12h i.v.; and on days 9 to 12, 4 mg/kg twice a day (b.i.d.) orally (p.o.). An interim
population pharmacokinetics analysis using data from the first 12 patients in
cohort 1 was used to determine which of two possible dosing regimens should be
followed for the second cohort of 18 patients.
A median AUC of approximately 40,000 ng ? h/ml was observed in 236 healthy
adult volunteers after an i.v. dose of 4 mg/kg q12h, and this was used as a
reference value (24). As predefined in the study protocol, if the interim analysis
revealed that the observed mean AUC was ?40,000 ng ? h/ml after the dosage of
6 mg/kg and if there were no safety concerns, then the next 18 patients would be
assigned to cohort 2 (on days 1 to 4, 6 mg/kg q12h i.v.; on days 5 to 8, 8 mg/kg
q12h i.v.; and on days 9 to 12, 6 mg/kg b.i.d. p.o.). If, however, the mean AUC
was ?40,000 ng ? h/ml, or if the AUC was ?40,000 ng ? h/ml but there were
safety concerns, then the next 18 patients would be assigned to cohort 2b (6
mg/kg q12h i.v. on day 1, 5 mg/kg q12h i.v., and then 4 mg/kg b.i.d. p.o. on days
5 to 8, followed by 5 mg/kg b.i.d. p.o. on days 9 to 12). If, on day 8 in cohort 1
or 2 or on day 4 in cohort 2b, the child was unable to take oral treatments, the
i.v. period could be extended until day 20. If there was a clinical need, patients
were allowed to continue voriconazole treatment until day 30. As summarized in
Table 1, the study ultimately enrolled patients into cohort 2.
The study was conducted in accordance with the ethical principals described in
the Declaration of Helsinki and received approval by institutional review boards
and independent ethics review committees. Investigators obtained written in-
formed consent from each patient’s parent or legal guardian. In addition, in-
formed assent also was obtained from the patient when this was possible.
Patients. Male and female patients aged from 2 to ?12 years of age who
required antifungal therapy for the prevention of invasive fungal infections and
who could, or were likely to, tolerate a transition from i.v. to oral therapy
between days 9 and 20 were eligible for enrollment into the study. Patients were
expected to develop neutropenia, defined as an absolute neutrophil count of
?500 cells/?l lasting more than 10 days, either as a result of chemotherapy for
leukemia, lymphoma, or aplastic anemia or in response to preparative treatment
for bone marrow or hematopoietic stem cell transplantation. Patients with a
history of hypersensitivity or severe intolerance to azole antifungal agents were
ineligible, as were those with a creatinine clearance of ?30 ml/minute or a history
or current evidence of cardiac arrhythmia. While concomitant drug use with
some drugs that potentially interact with voriconazole was permitted in accor-
dance with appropriate monitoring and dosage adjustment, patients who were
receiving terfenadine, pimozide, quinidine, astemizole, cisapride, omeprazole, or
ergot alkaloids and who could not discontinue these drugs at least 24 h before
starting the study, or who would need to receive any of these drugs during the
study, were excluded. Similarly, those patients who received rifampin, rifabutin,
carbamazepine, phenytoin, nevirapine, long-acting barbiturates, or sirolimus in
the 14 days prior to the start of the study were excluded. Patients with laboratory
safety findings at screening of aspartate aminotransferase (AST), alanine ami-
notransferase (ALT), or total bilirubin ?5 times the upper limit of normal were
ineligible. During the study, patients with breakthrough fungal infections, grade
III to IV toxicity according to the Common Toxicity Criteria of the National
Cancer Institute (http://ctep.cancer.gov/reporting/CTC-3test.html), or any other
clinically significant condition were discontinued from the study and were inel-
igible for dose escalation. Any patient enrolled into the study who subsequently
withdrew from participation was considered to be a discontinuation.
Procedures. This was a 30-day study consisting of a pharmacokinetic period
from day 1 to 12 and an optional nonpharmacokinetic period from day 13 to 30.
Patients returned to the study center at 23 to 37 days after their last voriconazole
dose for a follow-up visit. A physical examination was performed at screening, at
the end of therapy (EOT), and at the follow-up visit. The following visual
function tests were performed by an ophthalmologist: visual acuity (using Snellen
letters or charts), fixation (for patients too young to undergo visual acuity test-
ing), color vision (using the Ishihara test), visual field testing (for patients older
than 5 years), and funduscopy (for all patients). Blood and urine samples were
collected from each patient before the study and then again every 5 to 7 days or
for abnormal laboratory results until normalization. An additional blood sample,
or a buccal swab in those with profound neutropenia, was collected to determine
CYP2C19 genotype, which was identified in a central laboratory.
Voriconazole administration and formulations. i.v. voriconazole at a final
concentration of 2 mg/ml was administered at an infusion rate of 3 mg/kg/h.
Hence, the 4-, 6-, and 8-mg/kg dosages were administered over periods of 80,
120, and 160 min, respectively, every 12 h. Voriconazole powder for oral sus-
pension at a concentration of 40 mg/ml was administered 1 h before or after a
meal. Each dosage was provided for a minimum of 4 days.
Pharmacokinetic sampling. Blood samples for determination of voriconazole
concentrations were collected on day 4 of each dosing regimen at the following
times: before the dose; after i.v. doses of 4 mg/kg and 6 mg/kg, at 2 min before
the end of infusion and 2, 4, 6, 8, and 12 h after the start of the infusion; after the
i.v. dose of 8 mg/kg, at 2 min before the end of infusion and 4, 6, 8, and 12 h after
the start of the infusion; and after the oral dose, at 0.5, 1, 2, 4, 6, 8, and 12 h of
dosing. Samples were centrifuged at 1,500 ? g for 10 min at 4°C and submitted
to a central laboratory.
Nominal sampling times were used for pharmacokinetic calculations. In this
study, there was a total of 857 concentration points collected at steady state.
Approximately 97% of these samples were drawn within 10% of the nominal
sampling time. The 29 remaining samples (3.4%) from 14 subjects had a devia-
tion of over 10% from the nominal time. Twenty of these 29 samples had a
deviation within 25%. These deviations were found to have a minor impact on
the calculated AUC.
Pharmacokinetic analysis. Voriconazole and its major metabolite N-oxide
were assayed using a previously validated high-performance liquid chromatog-
raphy (HPLC) method (22). The lower limit of quantification was 10 ng/ml;
concentrations of below 10 ng/ml were set to zero for the analysis of means. The
accuracy and precision of the HPLC assay were ?10%. Plasma concentrations in
each cohort at each nominal time postdose were summarized as the mean,
standard deviation, and coefficient of variation. The area under the plasma-
concentration time curve over the dosing interval (AUC?) and the plasma con-
centration at the end of the i.v. infusion (CEOI) for the i.v. formulation and the
AUC?, maximum observed plasma concentration (Cmax), and time to first oc-
currence of Cmax(Tmax) for the oral suspension formulation were summarized by
dosage, age group, and cohort, and the bioavailability (F) was estimated using
noncompartmental analyses for each dosage.
Safety analysis. All adverse events (AEs) were recorded, regardless of treat-
ment group or suspected causal relationship to the study drug. Serious adverse
events (SAEs) included any event identified as serious according to predefined
criteria or any adverse experience that was considered serious by the investigator
or industrial sponsor. As this study devoted considerable attention to character-
TABLE 1. Dosing schedules
Cohort 1Cohort 2
2 to 4
5 to 8a
9 to 11
Up to 30
4 q12h i.v.
6 q12h i.v.
4 q12h p.o.c
4 q12h p.o.c
To continue on
voriconazole if there was
a medical need
6 q12h i.v.
8 q12h i.v.
6 q12h p.o.
6 q12h p.o.
To continue on
voriconazole if there was
a medical need
aIf the patient was unable to take oral medication, this period could be
extended up to day 20. Blood samples were taken on day 4 of this period.
bDay 4 of oral dosing. Patients switching to oral suspension on days 10 to 20
had blood samples drawn for pharmacokinetic analysis on days 13 to 23, respec-
tively, such that all of these patients received 4 days of the oral suspension,
irrespective of the day of switch.
VOL. 54, 2010 PHARMACOKINETICS OF VORICONAZOLE IN CHILDREN4117
izing visual AEs in detail, the events are described in this report as all-causality
nonvisual AEs and as all-causality visual AEs.
All deaths were reported immediately, regardless of elapsed time between last
time of dose of study drug and death. Blood samples were obtained at screening;
at days 4, 8, and 12; and at the 1-month follow-up visit for laboratory safety tests.
Statistical analysis. Data are expressed as mean ? standard deviation. Com-
parisons of proportions were performed by Fisher’s exact test. A P value of ?0.05
was considered to be significant. Analysis of the relationship between AUCs and
AEs are descriptive and are presented for generation of hypotheses for further
study of the association between voriconazole exposure and toxicity.
Baseline characteristics. Among 49 patients who were
screened, 48 (29 males and 19 females) from 12 centers in
three countries received voriconazole in two dosage cohorts of
24 patients each. The demographic characteristics of patients
in both cohorts were similar at baseline and are summarized in
Table 2. There were 18 patients in each dosage cohort who
completed all three dosing regimens. The total durations of
exposure to voriconazole following i.v. and oral dosing phases
were similar in the two cohorts, with median durations of 19
days (range, 3 to 26 days) in cohort 1 and 17 days (1 to 30 days)
in cohort 2. Durations of exposure at the highest i.v. dosage,
which coincided with the second dosing phase in cohorts 1 (6
mg/kg) and 2 (8 mg/kg), were also similar, with median values
of 10 days (2 to 16 days) and 9 days (4 to 17 days), respectively.
Patients in cohort 1 had a median nonpharmacokinetic dosing
period of 8 days (1 to 16 days), compared with 7 days (1 to 18
days) in cohort 2. The pattern of concomitant drugs, including
antibacterial agents, antiviral agents, cytotoxic chemotherapy,
corticosteroids, cyclosporine, and antiemetics, was consistent
with that expected for patients with immunosuppression and
malignancies and was similar for the two dosage cohorts. In
cohort 1, 16/24 (67%), 9/23 (39%), and 3/22 (14%) of patients
received concomitant cytotoxic agents during the three vori-
conazole dosing periods, respectively. Similarly, in cohort 2,
11/24 (44%), 7/22 (32%), and 2/20 (10%) patients received
concomitant cytotoxic drugs during the three voriconazole dos-
ing periods, respectively.
Pharmacokinetic analysis. Because the predefined refer-
ence median AUC value of 40,000 ng ? h/ml after 6 mg/kg q12h
i.v. was not achieved in cohort 1 and there were no concerns of
safety, the regimen planned for cohort 2 was followed. Mean
pharmacokinetic findings following i.v. and oral administration
of voriconazole in patients from both age groups after each
dosing regimen are shown in Table 3. There was high interpa-
tient variability in the pharmacokinetic parameters observed
following either i.v. or oral administration of voriconazole in
both cohorts. No significant differences in pharmacokinetic
parameters were observed between the younger (2 to ?6
years) and older (6 to ?12 years) age groups.
Plasma voriconazole concentrations increased in a dose-de-
pendent manner with i.v. or oral administration. The approx-
imately 3-fold increase in median AUC? of i.v. voriconazole
from 4 mg/kg to 8 mg/kg suggests nonlinear saturability. As
expected, in all dosing periods, the mean pharmacokinetic
parameters were higher in cohort 2 than in cohort 1 (Table 3
and Fig. 1). Within both cohorts, the median AUC? values of
i.v. voriconazole were similar in patients aged 2 to 5 years and
patients aged 6 to 11 years, with exception of the 8-mg/kg i.v.
dosage in cohort 2, where older patients demonstrated higher
levels of exposure.
After oral administration of voriconazole, peak concentra-
tions were observed between 1 and 3 h and between 30 min and
1 h after i.v. administration of voriconazole parenteral solution
(Fig. 1). After oral administration of voriconazole, children
aged 2 to ?6 years tended to have lower peak concentrations
and AUCs than those aged 6 to ?12 years. The oral bioavail-
ability of approximately 65% was similar after administration
of 4-mg/kg and 6-mg/kg suspensions.
Safety evaluation. (i) All-causality nonvisual adverse events.
Table 4 describes all-causality nonvisual AEs observed in at
least three patients in either cohort. There was no consistent
pattern between the dosing regimen and the frequency of all-
causality AEs. In addition, an analysis by voriconazole expo-
sure (?40,000 ng ? h/ml and ?40,000 ng ? h/ml) showed no
consistent association between exposure and the frequency of
all-causality AEs. The most commonly reported all-causality
nonvisual AEs were mucositis, fever, rash, hypertension, and
pruritus. Most AEs were mild to moderate, and the AE pro-
files were similar in the two cohorts, with the exceptions that
mucositis and pruritus were more common in cohort 1 than
cohort 2 and rash, edema, and epistaxis were more common in
TABLE 2. Baseline demographic data
(n ? 24)
(n ? 24)
Mean age, yrs (SD) ?n?
3.7 (1.2) ?12?
8.7 (1.9) ?12?
2.8 (1.1) ?12?
8.1 (1.4) ?12?
Mean wt, kg (range)
(all, 2–?6 yr, 6–?12 yr)
15, 7, 8
8, 5, 3
0, 0, 0
1, 0, 1
21, 9, 12
2, 2, 0
1, 1, 0
0, 0, 0
aEM, homozygous extensive metabolizer; HEM, heterozygous extensive me-
tabolizer; PM, homozygous poor metabolizer.
bPreparative regimen for bone marrow or hematopoietic stem cell transplan-
4118WALSH ET AL.ANTIMICROB. AGENTS CHEMOTHER.
cohort 2 than cohort 1. Skin-related events (rash and pruritus)
were seen in 13 patients in cohort 1 and 12 in cohort 2.
(ii) All-causality visual adverse events and function. As de-
scribed in Table 5, seven (29%) of 24 patients in cohort 1 and
two (8%) of 24 patients in cohort 2 experienced an all-causality
visual AE. In both cohorts, patients ?6 years old reported
fewer visual AEs than patients aged 6 to ?12 years old. The
frequencies of visual AEs did not increase with increasing
voriconazole exposure, as most events were reported at an
AUC value of ?40,000 ng ? h/ml. A single patient in each
cohort complained of a treatment-related visual AE. The first
such patient, a 2-year-old male in cohort 1, had moderate
photophobia, which was attributed to voriconazole and which
lasted several days after initiation of the second i.v. treatment.
The second patient, a 9-year-old female in cohort 2, experi-
enced intermittent blurred vision, which also was attributed to
voriconazole and which lasted for several days after each dos-
ing phase. However, this patient also had a pineoblastoma and
optic neuropathy at screening and a history of a left lateral
visual field defect.
Among the 17 patients who had visual acuity data at baseline
and at the end of therapy or follow-up visit, one patient from
cohort 1 and three patients from cohort 2 experienced deteri-
oration. In the opinion of the ophthalmologist, visual acuity
deterioration was related to “tiredness” (lack of cooperation
with the exam) or underlying illness in two of the patients,
while no relevant comments were provided for the two remain-
ing patients. All fixation tests were normal. There was only one
patient, the aforementioned 9-year-old female with pineoblas-
toma in cohort 2, whose normal baseline color vision test
became abnormal, in the left eye, at the 1-month follow-up
visit. Eight patients, six in cohort 1 and two in cohort 2, with a
normal baseline funduscopy test result returned an abnormal
result after receiving the study drug, but in each case the
abnormality was attributed to underlying conditions. Com-
pared with baseline, no patients had changes in their color
vision tests at EOT or at the 1-month follow-up visit.
(iii) Serious adverse events. Eight patients experienced a
serious AE during treatment with voriconazole, none of which
were assessed by the investigators as treatment related. Ten
patients experienced a posttherapy serious AE within 30 days
of the last dose of study drug. The minimum AUC value of 875
ng ? h/ml in the ?40,000 ng ? h/ml category and the maximum
AUC value of 178,000 ng ? h/ml in the ?40,000 ng ? h/ml cat-
egory both occurred in patients treated in cohort 1. The max-
imum AUC value was observed in a 7-year-old male patient
who received chemotherapy in preparation for HSCT. While
the patient experienced a serious AE of worsening pericardial
effusion, this was thought to be related to the immunosuppres-
sive regimen. This patient completed the study.
(iv) Treatment-related adverse events and study discontinu-
ations. The most common drug-related AEs were increased
cyclosporine concentrations and increased gamma glutamyl
transpeptidase (GGTP) levels; visual disturbances were un-
common. Four patients (16.6%) from cohort 1 and nine pa-
tients (37.5%) from cohort 2 experienced a treatment-related
AE (P ? 0.19). Of these, two in cohort 1 and five in cohort 2
had hepatic-related events. Eleven patients had mild to mod-
erate treatment-related AEs, while two in cohort 2 experienced
severe treatment-related AEs. One, a 5-year-old male, had a
TABLE 3. Pharmacokinetic parameters following i.v. and oral administration of voriconazole in patients in different age groups
Patient age (yr)
Value (n) ?coefficient of variation, %?
4 mg/kg i.v.
6 mg/kg i.v.
4 mg/kg p.o.
6 mg/kg i.v.
8 mg/kg i.v.
6 mg/kg p.o.
AUC? (ng ? h/ml)a
11,722 (12) ?76?
21,931 (11) ?125?
3,788 (10) ?78?
18,216 (10) ?87?
25,566 (10) ?81?
6,959 (9) ?104?
3,352 (12) ?71?
4,690 (11) ?111?
956 (12) ?85?
4,609 (10) ?93?
4,804 (10) ?83?
1,433 (10) ?66?
1.36 (12) ?15?
1.97 (11) ?0?
1.50 (12) ?144?
1.97 (10) ?0?
2.63 (10) ?0?
1.00 (10) ?58?
43.6 (10) ?88?
63.4 (8) ?88?
AUC? (ng ? h/ml)
11,954 (10) ?78?
24,047 (10) ?129?
7,346 (9) ?60?
16,234 (9) ?66?
34,681 (10) ?81?
10,076 (9) ?56?
3,067 (11) ?64?
4,009 (10) ?88?
1,555 (9) ?54?
3,986 (10) ?67?
6,924 (10) ?123?
2,213 (9) ?49?
1.36 (11) ?16?
1.97 (10) ?0?
1.33 (9) ?82?
2.17 (10) ?30?
3.04 (10) ?22?
1.72 (9) ?98?
90.9 (9) ?86?
66.7 (7) ?53?
2–?12 (all patients)
AUC? (ng ? h/ml)
11,827 (22) ?75?
22,914 (21) ?125?
5,184 (19) ?71?
17,249 (19) ?80?
29,776 (20) ?82?
8,373 (18) ?80?
3,212 (23) ?67?
4,353 (21) ?103?
1,178 (21) ?70?
4,286 (20) ?85?
5,767 (20) ?121?
1,761 (19) ?57?
1.36 (23) ?15?
1.97 (21) ?0?
1.43 (21) ?122?
2.07 (20) ?22?
2.84 (20) ?18?
1.34 (19) ?93?
66.0 (19) ?97?
65.1 (15) ?70?
c—, not calculated.
VOL. 54, 2010PHARMACOKINETICS OF VORICONAZOLE IN CHILDREN4119
serum GGTP concentration increase after 8-mg/kg i.v. dosing.
The GGTP values decreased after completion of voriconazole,
but at the 1-month follow-up visit they were still abnormal. The
second, a 9-year-old girl, experienced severe pruritus on day 4
when she received an i.v. dose of 6 mg/kg. Despite this AE, her
dose was escalated to 8 mg/kg according to the study protocol,
and the event resolved on day 7.
A single patient from each cohort discontinued study drug
due to treatment-related AEs. In cohort 1, a 2-year-old male
with normal serum hepatic enzymes and bilirubin at baseline
discontinued study drug after 4 days of 4-mg/kg oral suspen-
sion due to a voriconazole-related increase of total bilirubin,
AST, ALT, and GGTP. At the 1-month follow-up visit, all had
decreased to slightly above normal values. In cohort 2, a
2-year-old male with elevated ALT and GGTP values at base-
line discontinued the study drug on day 15 of treatment after 5
days of 6-mg/kg oral suspension, due to voriconazole-related
hepatic transaminase elevation. At follow-up on day 46, the
ALT value had returned to baseline, while the GGTP value
was below that recorded at baseline. Three more patients from
cohort 1 and five patients from cohort 2 discontinued for rea-
sons not related to the study drug. Among these eight patients,
five patients withdrew consent; one patient discontinued on
day 12 because of tonic seizure, right hemiparesis, and lethargy
thought to be related to cyclosporine therapy; one patient with
acute myelogenous leukemia and septic shock discontinued
after 14 days of 6-mg/kg i.v. voriconazole due to hyperbil-
irubinemia that was considered to be related to the underlying
illness; and the last patient discontinued during the nonphar-
macokinetic period because her neutrophil count improved
sufficiently to warrant discontinuation of voriconazole therapy.
Initial pharmacokinetic studies in children demonstrated
that the standard adult dosage of 4 mg/kg q12 h of i.v. vori-
conazole resulted in approximately 3-fold-lower plasma expo-
sures in pediatric patients than in adults. Thus, a subsequent
pharmacokinetic study of higher dosages was critically needed
in order to understand the dosage of i.v. voriconazole in pedi-
atric patients that would approach the median adult plasma
exposure associated with the 4-mg/kg dosage that was effective
in treatment of invasive aspergillosis (9). This multicenter
study of the safety, tolerability, and plasma pharmacokinetics
of the parenteral formulation of voriconazole in immunocom-
promised pediatric patients is to our knowledge the first sys-
tematic investigation to study dosages of ?4 mg/kg of i.v.
voriconazole in children. This report also describes the first
assessment of the plasma pharmacokinetics of the pediatric
oral suspension of voriconazole.
The elimination of voriconazole in children was previously
found to be linear over the dosage range of 3 mg/kg q12h i.v.
and 4 mg/kg q12h i.v. (24). This current study was designed to
determine the plasma pharmacokinetics, safety, and tolerabil-
ity of i.v. voriconazole in dosages from 4 mg/kg q12h to 8 mg/kg
q12h, as well as to understand the pharmacokinetic properties
of the pediatric oral suspension. As previous studies of vori-
conazole have demonstrated marked interindividual variation
in plasma pharmacokinetic parameters but comparatively min-
TABLE 4. All-causality nonvisual adverse events reported for at
least three patients in either cohort 1 or cohort 2
1 (n ? 24) 2 (n ? 24)
Injection site complications
aAt least one all-causality adverse occurred in 24 of 24 patients in cohort 1 and
in 23 of 24 patients in cohort 2.
FIG. 1. Mean plasma voriconazole concentrations in cohort 1 (a) and cohort 2 (b).
4120WALSH ET AL.ANTIMICROB. AGENTS CHEMOTHER.
imal intraindividual variation, dosage escalation was conducted
within patients in this current study. Intrapatient dosage esca-
lation also permits the patient to serve as his or her own
control for the variables of body weight and CYP2C19 geno-
type. This approach permits a more reliable analysis of differ-
ences of plasma pharmacokinetics across the dosages 4 to 8
mg/kg q12h i.v. The same study design also allowed patients to
serve as their own controls for analysis of bioavailability of the
The clearance of voriconazole varies depending upon the
allelic polymorphisms of CYP2C19. Single-nucleotide poly-
morphisms in the gene encoding the protein of CYP2C19
result in two phenotypes: poor metabolizers (PMs) and exten-
sive metabolizers (7, 12). Extensive metabolizers are further
classified into homozygous (EM) and heterozygous (HEM)
populations. Approximately 15 to 20% of the Asian population
is comprised of PMs, while only 3 to 5% of the Caucasian and
African human population display this phenotype. While the
CYP2C19 genotype is the most important determinant of vori-
conazole clearance and a major factor in interpatient variabil-
ity, this genotypic classification does not adequately account
for the differences observed in drug exposure and clearance
between pediatric and adult patients. The greater clearance of
voriconazole in pediatric patients may be better explained by
the increased ratio of hepatic to total body mass in children or
perhaps by age-related differences in expression of CYP2C19
The study reported here demonstrates that over the range of
4 mg/kg q12h i.v. and 8 mg/kg q12h i.v., the elimination of
voriconazole in children is nonlinear. These findings compare
with those of adults, where the elimination of voriconazole
follows Michaelis-Menten-type saturation plasma pharmacoki-
netics over the dosage range of 3 and 4 mg/kg. As patients in
this study demonstrated wide intersubject variation and may
not have achieved steady state in all cases, calculation of Km
and Vmaxfor characterization of the nonlinear saturation phar-
macokinetic properties of voriconazole in this population
would not have been accurate.
By noncompartmental analysis, the mean AUC achieved in
adults following the currently recommended dosage of 4 mg/kg
was approximated in children receiving 8 mg/kg i.v. Within
both cohorts, the pharmacokinetic parameters of voriconazole
after i.v. dosing were similar in patients aged 2 to 5 years and
in patients aged 6 to 11 years; however, the older patients
receiving 8 mg/kg in cohort 2 demonstrated somewhat higher
levels of plasma exposures, perhaps related to diminished
clearance in the older population. Nevertheless, these pharma-
cokinetic observations are consistent with those of the earlier
pediatric study that examined the pharmacokinetics of i.v. vori-
conazole administered at 3 mg/kg b.i.d. and 4 mg/kg b.i.d.; that
study demonstrated no significant differences in Cmaxor AUC
between the 2- to 5-year and the 6- to 11-year age groups. After
oral dosing, older patients in the current study also had higher
median AUCs and Cmaxs than did younger patients in both
Voriconazole in adults is well absorbed, with bioavailability
reaching 96% (17). In this study, however, the bioavailability
was only approximately 66%, and there were no differences
between younger and older patients. The reasons for lower
bioavailability in children compared with adults are incom-
pletely characterized but may be related to developmental
differences in the activity of intestinal drug-metabolizing en-
zymes and efflux transporters.
The current study was conducted in immunocompromised
children in whom there was a high risk of developing invasive
fungal infection, which was predominantly associated with
treatment of the underlying neoplastic diseases with cytotoxic
chemotherapy or hematopoietic stem cell transplantation. The
number and type of all-causality AEs were typical for this
population; the AE profile was consistent with their underlying
conditions and concomitant treatments and was similar to that
seen in neutropenic adults. The types of AEs observed in this
study were similar to those in the earlier pediatric and adult
studies of voriconazole, where most events occurred in three
categories: hepatic, cutaneous, and visual.
Abnormalities in hepatic transaminases are known side ef-
fects of voriconazole and have been observed in 12 to 20% of
patients in previous studies (23). When all-causality liver
events were analyzed, there were no differences between co-
horts, nor were they different from those observed in the pre-
vious pediatric pharmacokinetic study (24). Moreover, when
liver-associated laboratory abnormalities, including increased
concentrations of serum hepatic transaminases and bilirubin,
are analyzed, their occurrence was the same in both dosage
cohorts and the frequency similar to that seen in immunocom-
promised adults treated with voriconazole (9, 14, 17, 26).
Although there were more patients with treatment-related
AEs in cohort 2 than in cohort 1 (9 versus 4), the number of
TABLE 5. All-causality visual adverse events and their attribution assigned by investigator
Cohort Age (yr)Gender Visual adverse event(s)Investigator-assigned attribution(s)
Mild dry eyes, moderate photophobia
Mild dry eyes, moderate eye hemorrhage
Moderate ocular hemorrhage, moderate
eye pain, moderate eye pain
Concomitant chemotherapy, voriconazole
Total body irradiation, thrombocytopenia
Concomitant retinoid treatment
Bone marrow transplant conditioning treatment
Air conditioning system
Thrombocytopenia, periorbital swelling, eyelash caught in eye11
11 MaleConcomitant cyclosporine treatment
29Female Mild worsening of blurred vision Worsening of preexisting condition (considered not to be
related to study drug and resolved spontaneously)
Voriconazole9 FemaleModerate blurred vision
VOL. 54, 2010PHARMACOKINETICS OF VORICONAZOLE IN CHILDREN4121
AEs was only slightly different (14 versus 11, respectively).
These differences were primarily associated with AEs related
to the liver (increased hepatic enzymes, hyperbilirubinemia,
and jaundice; 8 versus 5 events, respectively) and to the skin
(pruritis and rash; 2 versus 0 events, respectively). When the
distribution of AEs was analyzed as a function of plasma ex-
posure of voriconazole (?40,000 ng ? h/ml versus ?40,000
ng ? h/ml), the distribution of hepatic AEs was not different.
This finding is consistent with a previous analysis of 1,053
adults who had received standard dosages of voriconazole and
who demonstrated only a weak correlation between voricon-
azole plasma concentrations and AST, alkaline phosphatase,
or bilirubin but not ALT abnormalities (23).
With the exception of cases of pruritus and rash in two
patients in cohort 2 that were attributed by the investigator to
voriconazole, the other cutaneous-related events were related
to concomitant therapies, other illness, or to graft-versus-host
disease. The relatively high frequency of cutaneous-related
AEs in this study population, where approximately one-third of
patients were suffering from graft-versus-host disease and re-
ceiving multiple concomitant medications, is expected. Rash is
a known adverse reaction to voriconazole. The patterns of
cutaneous reactions to voriconazole include a solar hypersen-
sitivity that is well described in an ambulatory population (4)
but seldom observed among inpatients (26). Consistent with
these earlier observations, only 2 of 24 cutaneous AEs in this
study were associated primarily with voriconazole treatment.
In order to thoroughly determine the possible ocular effects
of voriconazole in pediatric patients, this study included a
robust range of visual function tests. Due to the young age of
the patients and the severity of disease in this population, there
were difficulties in completing all of the visual function tests,
particularly the visual field, visual acuity, and fixation tests.
Hence, an insufficient number of patients underwent the visual
field test to produce meaningful results. In addition, full visual
acuity data, including baseline and EOT or 1-month follow-up
tests, were available for only 17/48 patients, and full fixation
test results were collected for 26/48 patients. However, based
on the wide range of visual tests performed in this study, there
was no evidence that voriconazole treatment affected the de-
In this study, there were seven patients (29%) in cohort 1
and two (8%) in cohort 2 with all-causality visual AEs but only
two (4%) of 48 patients (one patient in each cohort) with
treatment-related visual AEs. While voriconazole may have
contributed to a decline in visual acuity, other concomitantly
administered agents, such as opiates for pain control, and lack
of cooperation in this pediatric oncology population also may
have contributed to impaired visual acuity. Supporting this
possibility was the lack of a relationship between increasing
voriconazole exposure and development of visual AEs. Of
those patients whose visual function tests changed from base-
line during the study, most changes could be attributed to
underlying conditions. These findings are consistent with the
previous pediatric pharmacokinetic study in which 3 (11%) of
28 patients experienced five voriconazole-related visual distur-
bances (eye pain, itchy eyes, photophobia, blurred vision, and
strabismus) (24). Although the frequencies of visual AEs in
this study and in adults are similar, there were no well-docu-
mented episodes of photopsia in the children studied here. By
comparison, photopsia constitutes the majority of visual AEs in
adults. This difference may be the result of underreporting of
photopsia by the children in this study. Nonetheless, all visual
events in this study and in the previous prospective trial were
transient and resolved without intervention.
Assessing attribution of ophthalmic, functional, and fundu-
scopic abnormalities in immunocompromised children is chal-
lenging. While photopsia and visual hallucinations are well
described in adults (26, 29), these complaints are not as com-
monly reported in children. This may be related in part to
difficulty in verbally describing these events in a younger pop-
ulation. For example, symptoms of photophobia may overlap
with those of photopsia. Yet another challenge is the ability to
discern common ophthalmic problems, such as conjunctivitis,
and nonspecific funduscopic changes, such as papilledema and
retinal hemorrhages, which may occur during antineoplastic
therapy or HSCT, from potential study drug effects. The fact
that there have been no consistent patterns of ophthalmic,
funduscopic, or visual defects observed in adults over time,
other than photopsia and visual hallucinations, provides some
cautious guide to interpreting attribution in children. The
mechanism of photopsia appears to be a transient neurochem-
ical effect, while the mechanism of visual hallucinations ap-
pears to be directly related to serum concentrations (29).
Recognizing the challenges of assessing attribution and con-
sidering the wide range of visual tests performed in this
study, there appears to be no evidence that voriconazole
treatment affected the developing eye.
There is increasing recognition of the importance of distin-
guishing the pharmacokinetic characteristics of compounds in
children and adults (6). As with other pharmacokinetic studies
of voriconazole in adults and children, this study showed high
levels of interpatient variability in pharmacokinetic parameters
(6, 17, 18, 24). Due to this high interpatient variability and
nonlinear pharmacokinetic profile, noncompartmental analysis
may not be appropriate for dosing recommendations for vori-
conazole. Therefore, the pharmacokinetic data from this study
and two other pediatric pharmacokinetic studies were investi-
gated further in a population-based pharmacokinetic analysis.
Based on an overall assessment of these aggregate data, a
population-based pharmacokinetic analysis, and the risk-ben-
efit analysis of unpredictably elevated circulating concentra-
tions, the European Agency for the Evaluation of Medicines
(EMEA) advocated the dosage of 7 mg/kg q12h i.v. voricon-
azole for life-threatening infections for children aged 2 to
The fact that this study and the earlier study of lower dos-
ages of 3 and 4 mg/kg (24) enrolled predominantly Caucasian
children is a limitation that warrants caution in dosage of
children of Asian ancestry. Both the descriptive pharmacoki-
netics reported in the present study and their model-based
analysis (13) are based upon a mostly non-Asian patient pop-
ulation. As children with Asian backgrounds may display a
poor metabolizer phenotype, careful therapeutic drug moni-
toring may be especially important in this population in order
to avoid potentially toxic serum concentrations.
Underscoring the need for accurate dosing of voriconazole
in immunocompromised children, Neeley and colleagues iden-
tified a pharmacodynamic association between a voriconazole
trough of ?1,000 ng/ml and survival (15). The fact that the
4122WALSH ET AL.ANTIMICROB. AGENTS CHEMOTHER.
pharmacokinetics of voriconazole in children is characterized
by wide interpatient variation (13, 15, 24) warrants the use of
therapeutic drug monitoring in patients with invasive aspergil-
losis and other life-threatening invasive fungal infections in
order to attain therapeutic levels while avoiding toxicity (1).
In summary, this report describes the plasma pharmacoki-
netics of higher dosages of voriconazole needed to treat an
immunocompromised pediatric patient population with expo-
sures comparable to those of adult patients. In order to attain
exposure of voriconazole in plasma comparable to that
achieved with the 4-mg/kg i.v. dosage in adults, children aged
2 to 11 years old would need a dosage approaching 8 mg/kg.
The study also demonstrates that the oral bioavailability of
voriconazole in children is much lower than that in adults,
suggesting the need for higher weight-adjusted oral dosages
than those used for i.v. treatment. However, due to very high
interpatient variability and the nonlinear pharmacokinetic pro-
file of voriconazole, formal dosing recommendations cannot be
based solely on noncompartmental analysis. Instead, a popu-
lation-based pharmacokinetic model should guide such formal
dosing recommendations. Nevertheless, when combined with
an overall favorable safety profile indicating the absence of
dose-dependent toxicity and the current exposure profiles, the
current data reported here indicate that a dosage of voricon-
azole of approximately 8 mg/kg i.v. provides comparable and
safe exposure in immunocompromised pediatric patients.
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