ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 1998, p. 404–408 Vol. 42, No.

2
0066-4804/98/$04.0010
Copyright © 1998, American Society for Microbiology

Repeated-Dose Pharmacokinetics of an Oral Solution of

Itraconazole in Infants and Children
LOUIS DE REPENTIGNY,1* JOHANNE RATELLE,1 JEAN-MARIE LECLERC,2 GUY CORNU,3
ÉTIENNE M. SOKAL,3 PHILIPPE JACQMIN,4 AND KAREL DE BEULE4
Department of Microbiology and Immunology,1 and Division of Hematology and Oncology,2 Sainte-Justine
Hospital and University of Montreal, Montreal, Quebec, Canada, and Department of Pediatrics, University of
Louvain Medical School, Brussels,3 and Janssen Research Foundation, Beerse,4 Belgium
Received 28 April 1997/Returned for modification 28 August 1997/Accepted 9 November 1997

The safety, tolerability, and pharmacokinetics of an oral solution of itraconazole and its active metabolite
hydroxyitraconazole were investigated in an open multicenter study of 26 infants and children aged 6 months
to 12 years with documented mucosal fungal infections or at risk for the development of invasive fungal disease.
The most frequent underlying illness was acute lymphoblastic leukemia, except in the patients aged 6 months
to 2 years, of whom six were liver transplant recipients. The patients were treated with itraconazole at a dosage
of 5 mg/kg of body weight once daily for 2 weeks. Blood samples were taken after the first dose, during
treatment, and up to 8 days after the last itraconazole dose. On day 1, the mean peak concentrations in plasma
after the first and last doses (Cmax) and areas under the concentration-time curve from 0 to 24 h (AUC0–24) for
itraconazole and hydroxyitraconazole were lower in the children aged 6 months to 2 years than in children aged
2 to 12 years but were comparable on day 14. The mean AUC0–24-based accumulation factors of itraconazole
and hydroxyitraconazole from day 1 to 14 ranged from 3.3 to 8.6 and 2.3 to 11.4, respectively. After 14 days of
treatment, Cmax, AUC0–24, and the half-life, respectively, were (mean 6 standard deviation) 571 6 416 ng/ml,
6,930 6 5,830 ng z h/ml, and 47 6 55 h in the children aged 6 months to 2 years; 534 6 431 ng/ml, 7,330 6 5,420
ng z h/ml, and 30.6 6 25.3 h in the children aged 2 to 5 years; and 631 6 358 ng/ml, 8,770 6 5,050 ng z h/ml,
and 28.3 6 9.6 h in the children aged 5 to 12 years. There was a tendency to have more frequent low minimum
concentrations of the drugs in plasma for both itraconazole and hydroxyitraconazole for the children aged 6
months to 2 years. The oral bioavailability of the solubilizer hydroxypropyl-b-cyclodextrin was less than 1% in
the majority of the patients. In conclusion, an itraconazole oral solution given at 5 mg/kg/day provides
potentially therapeutic concentrations in plasma, which are, however, substantially lower than those attained
in adult cancer patients, and is well tolerated and safe in infants and children.

Invasive fungal infections are a growing cause of morbidity 250 ng/ml in adult patients during autologous bone marrow
and mortality in infants and children with hematological ma- transplantation (13) or during remission induction for acute
lignancies or undergoing liver transplantation (12, 19). These myeloblastic leukemia (14). These concentrations of itracon-
infections are most frequently caused by Candida or Aspergillus azole in serum were judged to be suitable for antifungal pro-
species (12, 19). Unfortunately, treatment of these invasive phylaxis because of data suggesting an excess of episodes of
mycoses is complicated by problems in diagnosis (4, 19) and invasive pulmonary aspergillosis in patients whose maximum
the limited efficacy and toxicities of available systemic antifun- concentrations of the drug in serum were less than 250 ng/ml
gal agents (19). Itraconazole is an orally active triazole anti- (1). However, pharmacokinetic data on itraconazole in chil-
fungal agent with a wide spectrum of activity and pronounced dren are limited, and questions with regard to dosage sched-
lipophilic properties (17, 18). The pharmacokinetics of itracon- ules in prevention and treatment of systemic fungal infections
azole in healthy adult volunteers are characterized by good often arise. The objective of the present study was to assess the
oral absorption, an extensive tissue distribution with concen- pharmacokinetics of itraconazole and its active metabolite hy-
trations in tissue considerably higher than in plasma, a rela- droxyitraconazole during and after repeated dosing of itracon-
tively long elimination half-life (t1/2) (about 1 day), and bio- azole in oral solution, 5 mg/kg per day for 2 weeks, in infants
transformation into a large number of metabolites (7, 8, 16). and children requiring systemic antifungal prophylaxis or treat-
Itraconazole is thus potentially useful in the prophylaxis or ment.
treatment of invasive candidiasis or aspergillosis in immuno-
compromised children. However, the available capsule formu-
MATERIALS AND METHODS
lation of itraconazole may be difficult to administer to infants
and children. Recently, a 10-mg/ml oral solution of itracon- Patients. Male and female children aged 6 months to 12 years with a docu-
mented mucosal fungal infection or at risk for the development of invasive fungal
azole was developed, with hydroxypropyl-b-cyclodextrin as a disease were eligible for this study. Their hospitalization was planned for at least
solubilizer. With a dosage of 5 mg/kg of body weight once daily, 14 days after the first itraconazole dose. The protocol was approved by the ethics
maximum concentrations in serum of itraconazole exceeded committee of each participating center, and written informed consent was ob-
tained from the children’s legal representatives.
Patients were excluded if any of the following applied: concomitant use of
other systemically absorbed antifungal drugs; treatment with rifampin, phenyt-
* Corresponding author. Mailing address: Department of Microbi-
oin, phenobarbital, carbamazepine, terfenadine, astemizole, warfarin, rifabutin,
ology and Immunology, Sainte-Justine Hospital and University of cisapride, or loratadine concomitantly or in the 2 weeks prior to start of the
Montreal, 3175 Côte Sainte-Catherine, Montreal, Quebec, Canada itraconazole treatment; a known sensitivity to the azole groups of antifungals;
H3T 1C5. Phone: (514) 345-4643. Fax: (514) 345-4860. E-mail: louisr signs of hepatic dysfunction defined by liver function test results greater than
@globale.net. three times the laboratory’s normal ranges, unless etiologically well documented

404
VOL. 42, 1998 ITRACONAZOLE ORAL SOLUTION IN CHILDREN 405

TABLE 1. Demographic characteristics, diagnoses, and intercurrent diseases

Age (yr)
Characteristics Total
0.5–2 2–5 5–12

Patients 8 7 11 26
Male, n (%) 4 (50) 5 (71.4) 9 (81.8) 18 (69.2)
Female, n (%) 4 (50) 2 (28.6) 2 (18.2) 8 (30.8)
Age, mo (mean 6 SD) 14.6 6 2.2 44.1 6 3.9 89.9 6 8.2 54.4 6 7.4
Ht, cm (mean 6 SD) 73.8 6 3.4 100.2 6 2.7 119.5 6 4.2 100.2 6 4.4
Wt, kg (mean 6 SD) 8.7 6 1.0 15.3 6 1.1 23.9 6 2.4 16.9 6 1.7

Diagnosis, n (%)
Mucosal yeast infection 3 (37.5) 0 (0) 0 (0) 3 (11.5)
Prophylaxis 5 (62.5) 7 (100) 11 (100) 23 (88.5)

Intercurrent disease, n (%)

Acute lymphoblastic leukemia 2 (25) 4 (57.1) 6 (54.5) 12 (46.2)
Orthotopic liver transplantation 6 (75) 6 (23.1)
Acute myeloblastic leukemia 2 (28.6) 2 (7.7)
Acute monocytic leukemia 1 (14.3) 1 (3.8)
Burkitt’s lymphoma 1 (9.1) 1 (3.8)
Neuroblastoma 2 (18.2) 2 (7.7)
Relapse of lymphoma 1 (9.1) 1 (3.8)
Myelodysplastic syndrome 1 (9.1) 1 (3.8)

in cases of liver transplantation; and participation in an investigational drug trial, RESULTS

except for chemotherapy and growth factor trials, within 30 days prior to the start
of the trial. Twenty-six patients were recruited, of whom eight were be-
Drug administration. Patients were treated with itraconazole at dosages of 5 tween 6 months and 2 years old, seven were 2 to 5 years old,
mg/kg once daily for 14 days, provided in an oral solution containing 10 mg of and 11 were 5 to 12 years old. During the open treatment
itraconazole per ml and 400 mg of hydroxypropyl-b-cyclodextrin per ml. The
required volume was either pipetted directly into the mouth or given to the child
to drink with water. Whenever possible, the dose was given after an overnight
fast and at least 30 min before breakfast.
Pharmacokinetic and safety assessments. Venous blood samples (2 ml) for the
measurement of itraconazole and its active metabolite hydroxyitraconazole were
taken through a central catheter immediately before the first dose; 2, 4, 8, and
24 h after the first dose; immediately before the dose on days 5, 8, and 11;
immediately before the last dose; 2, 4, 8, and 24 h after the last dose; and 2, 3,
5, and 8 days after the last dose. Blood was collected into heparinized tubes and
centrifuged for 10 min at 1,000 3 g within 2 h. Plasma was stored at 220°C until
required for assay. Itraconazole and hydroxyitraconazole were measured by
high-performance liquid chromatography with UV detection (20). The limit of
quantification was 5 ng/ml for itraconazole and 10 ng/ml for hydroxyitraconazole.
The mean coefficients of variation were 3.4, 1.3, and 1.9% for itraconazole at
concentrations in plasma of 15, 95, and 600 ng/ml, respectively. For hydroxyitra-
conazole, the coefficients of variation were 6.1, 2.8, and 3.4% at the same
concentrations in plasma.
Whenever possible, a predose urine sample and the complete urinary output
during the intervals 0 to 8 h and 8 to 24 h after the first and last dose of
itraconazole were collected for measurement of hydroxypropyl-b-cyclodextrin.
Urine volume and pH were recorded, and a 20-ml sample was stored at 220°C
before analysis. Hydroxypropyl-b-cyclodextrin was measured by size exclusion
chromatography with postcolumn complexation (15). The limit of detection was
1 mg/ml, and the coefficients of variation were 6.3, 4.5, 2.9, and 10.8% at con-
centrations of 3, 30, 150, and 300 mg/ml, respectively.
Data on adverse events were collected throughout the study. In addition, blood
was collected for hematological and biochemical tests within 1 week before the
first dose of itraconazole and 24 h after the last dose.
Data analyses. Based on the plasma concentration-time curves of individual
patients, the following pharmacokinetic parameters were determined for itra-
conazole and hydroxyitraconazole: minimal (predose) concentration in plasma
(Cmin); peak concentration in plasma after the first and last dose (Cmax); time to
attain Cmax (Tmax); area under the plasma concentration-time curve of a dosing
interval after the first and last dose (AUC0–24), determined by trapezoidal sum-
mation (6); metabolic ratio, calculated as the AUC0–24 for hydroxyitraconazole
divided by the AUC0–24 for itraconazole (ratiomet); accumulation factor, calcu-
lated as the AUC0–24 for the last dose divided by the AUC0–24 for the first dose
(R); elimination rate constant after the last dose (6); and terminal t1/2 after the
last dose (t1/2term). The amount of hydroxypropyl-b-cyclodextrin excreted in the FIG. 1. Semilogarithmic plot of the mean concentrations in plasma of itra-
urine was calculated by multiplying the concentration in urine by the volume of conazole and hydroxyitraconazole as a function of time after oral administration
urine. of itraconazole in oral solution, 5 mg/kg/day, for 2 weeks to children.
406 DE REPENTIGNY ET AL. ANTIMICROB. AGENTS CHEMOTHER.

TABLE 2. Pharmacokinetic parameters of itraconazole and hydroxyitraconazolea

Itraconazole

Day 1 Day 14
Age (yr)
Cmax AUC Predose concn Cmax AUC
Tmax (h) Tmax (h) R t1/2term (h)
(ng/ml) (ng z h/ml) (ng/ml) (ng/ml) (ng z h/ml)

0.5–2 2.9 6 1.1 138 6 91 1,340 6 780 159 6 218 1.9 6 0.1 571 6 416 6,930 6 5,830 6.2 6 5.0 47.4 6 55.0
2–5 2.4 6 0.8 314 6 105 2,740 6 1,080 179 6 101 2.9 6 2.5 534 6 431 7,330 6 5,420 3.3 6 3.0 30.6 6 25.3
5–12 2.8 6 1.8 298 6 292 2,010 6 1,580 223 6 145 3.1 6 2.1 631 6 358 8,770 6 5,050 8.6 6 7.4 28.3 6 9.6
a
Data are means 6 standard deviations.

period, three patients in the group of those aged 5 to 12 years period, adverse events occurred in two patients in the group of
dropped out. Two patients with acute lymphoblastic leukemia those aged 6 months to 2 years, five occurred in the group of
and neuroblastoma, respectively, withdrew on days 10 and 7 those aged 2 to 5 years, and six occurred in the group of those
because of fever, which was considered a prophylactic end- aged 5 to 12 years. Adverse events occurring in at least three
point, and were given intravenous amphotericin B. A third patients in any group are shown in Table 3. The incidence of
patient, with acute lymphoblastic leukemia, dropped out on adverse events was higher in patients aged 5 to 12 years. No
day 6 because of lack of cooperation in taking the medication. treatment-related severe or serious adverse events occurred.
In addition, one patient with acute lymphoblastic leukemia in All patients showed abnormal laboratory data at some time
the same age group discontinued taking the medication be- during treatment but no consistent, clinically relevant changes
cause of vomiting on day 11 only but continued to have assess- were observed. In the group of those aged 6 months to 2 years,
ments. During the run-out period, one patient in the group of high values for alanine aminotransferase, aspartate amino-
those aged 6 months to 2 years dropped out due to an inter- transferase, and gamma-glutamyl transferase were observed in
current event (the patient moved). The demographic charac- three liver transplant patients but were considered normal at
teristics and diagnoses of the patients are summarized in Table that stage after transplantation. Increases in these parameters
1. The most frequent intercurrent illness was acute lympho- were also noted in two patients with acute lymphoblastic leu-
blastic leukemia, except in the patients aged between 6 months kemia in the group of those aged 2 to 5 years but were attrib-
and 2 years, of whom six were liver transplant recipients. All uted to antineoplastic chemotherapy. Finally, a borderline in-
patients were neutropenic, except those who underwent a liver crease in alanine aminotransferase in a patient with acute
transplantation. lymphoblastic leukemia in the group of those aged 5 to 12
The time courses of the mean concentrations of itraconazole years was considered to be possibly related to itraconazole.
and hydroxyitraconazole in plasma are shown in Fig. 1. The
pharmacokinetic parameters of itraconazole and hydroxyitra- DISCUSSION
conazole are summarized in Table 2. On day 1, the mean Cmaxs
and AUC0–24s of itraconazole and hydroxyitraconazole were Itraconazole has a broader spectrum of activity than the
lower for the group of those aged 6 months to 2 years than for other azoles and is the only commercially available antifungal
the other two groups but were comparable on day 14. The in this class with in vitro activity against Aspergillus. Clinical
same pattern was observed for the mean ratiomet. The Tmaxs efficacy of itraconazole has been shown in adult patients with
were comparable in the three age groups and did not change candidal thrush or esophagitis (5) and inferred in patients with
significantly during repeated doses. The mean AUC0–24-based invasive aspergillosis (3). It is thus potentially useful in the
accumulation factor of itraconazole and hydroxyitraconazole prophylaxis and treatment of mucosal and invasive fungal in-
from day 1 to 14 ranged from 3.3 to 8.6 and 2.3 to 11.4, fections in children. This first pharmacokinetic study of itra-
respectively. There was a tendency to have more frequent low conazole oral solution in children was prompted by potential
Cmins for both itraconazole and hydroxyitraconazole in the differences between children and adults, as illustrated by the
group of those aged 6 months to 2 years. The t1/2term values shorter t1/2 of fluconazole in serum in children with neoplastic
measured at steady state were comparable in the three age diseases than in adults (10).
groups for both itraconazole and hydroxyitraconazole. The pharmacokinetics of the itraconazole capsule prepara-
In the majority of patients (11 of 14), less than 1% of the tion have been well defined in healthy adult volunteers and
hydroxypropyl-b-cyclodextrin dose was excreted in the urine immunocompromised patients. In healthy volunteers, intake of
on days 1 and/or 14. In the other three patients (one in the the capsules after a meal enhanced bioavailability (8). In dif-
group of those aged 2 to 5 years and two in the group of those ferent studies, oral dosing of 100 mg once daily for 2 weeks
aged 5 to 12 years), the percentage of the hydroxypropyl-b- produced mean Cmaxs of 378 and 672 ng/ml, AUC0–24s of 5,330
cyclodextrin dose excreted in the urine did not exceed 11.8%. and 9,416 ng z h/ml, a t1/2 of 34 h, and a Tmax of 3 h (7, 8, 16),
Given that after intravenous administration 80 to 90% of the but wide intersubject variations were observed. Steady state
dose is excreted unchanged in the urine (9), the mean oral was attained in 10 to 14 days, and oral bioavailability was
bioavailability of hydroxypropyl-b-cyclodextrin in the majority disproportionately augmented by increasing the dose. Much
of the patients can be estimated to be less than 1%. lower itraconazole concentrations were attained in patients
During the open treatment period, adverse events—mainly with acute leukemia or autologous bone marrow transplanta-
gastrointestinal system and general disorders—were reported tion than in healthy volunteers (2, 11). In one study (2), re-
for all patients, except for two in the group of those aged 6 peated doses of 200 mg of the itraconazole capsule preparation
months to 2 years. The most frequent adverse event was vom- once daily for 2 weeks produced a mean Cmax of 412 ng/ml and
iting, which is also reported for adult cancer patients treated an AUC0–24 of 6,040 ng z h/ml, compared to 1,028 ng/ml and
with itraconazole in oral solution (13, 14). During the run-out 15,400 ng z h/ml in healthy adult volunteers (7). Capsules are
VOL. 42, 1998 ITRACONAZOLE ORAL SOLUTION IN CHILDREN 407

TABLE 2—Continued
Hydroxyitraconazole

Day 1 Day 14

Cmax AUC Predose concn Cmax AUC

Tmax (h) Ratiomet Tmax (h) R Ratiomet t1/2term
(ng/ml) (ng z h/ml) (ng/ml) (ng/ml) (ng z h/ml)

3.9 6 2.7 179 6 101 2,340 6 1,490 1.6 6 0.6 308 6 436 4.4 6 2.3 690 6 445 13,200 6 11,400 11.4 6 16.0 1.7 6 0.7 18.0 6 18.1
4.1 6 2.7 493 6 106 6,730 6 1,950 2.6 6 0.6 487 6 314 4.8 6 2.7 687 6 419 13,400 6 9,110 2.3 6 1.9 2.1 6 0.7 17.1 6 14.5
3.1 6 1.8 447 6 365 4,920 6 4,390 2.4 6 0.6 437 6 246 10.8 6 14.3 699 6 234 13,450 6 7,190 6.4 6 5.6 1.7 6 0.5 17.9 6 8.7

thus poorly absorbed in neutropenic cancer patients at greatest dren with neoplastic disease than in adults most likely resulted
risk of fungal disease. Accordingly, an oral solution of 10 mg of from decreased absorption from the gastrointestinal tract, be-
itraconazole per ml and 400 mg of hydroxypropyl-b-cyclodex- cause of either mucositis or vomiting. The relative contribu-
trin per ml which improves bioavailability by as much as 30% tions of age and underlying disease to the observed lower levels
when administered to healthy volunteers (data on file; Janssen in the patients aged 2 to 12 years than in adults cannot be
Research Foundation) was developed. In contrast to the cap- determined from the present study and will require pharma-
sule formulation, itraconazole in oral solution does not need to cokinetic data in healthy volunteers from this same age group.
be administered with food (data on file; Janssen Research However, children with neoplastic disease may require higher
Foundation), and Tmax is attained more rapidly (8). Repeated- doses on a milligram-per-kilogram basis than adults for equiv-
dose pharmacokinetics of itraconazole in oral solution, 5 mg/kg alent prophylactic and therapeutic benefits. Because the phar-
daily, were essentially identical in adult autologous bone mar- macokinetics of itraconazole are related nonlinearly to dose, it
row transplant recipients (13) and patients receiving chemo- would be worthwhile to investigate the pharmacokinetics at
therapy for acute myeloid leukemia (14). After 2 weeks, mean higher doses in defined populations of immunocompromised
Cmaxs were 1,464 and 1,486 ng/ml, and mean AUC0–24s were children. It would be difficult to unequivocally state that the
24,476 and 22,710 ng z h/ml, respectively, for these two groups itraconazole levels obtained at 5 mg/kg daily in this study are
of patients. Achievable concentrations in serum were thus con- therapeutic, since correlations between levels and outcome are
siderably improved in adult neutropenic cancer patients receiv- sparse (1). However, since lower levels are achieved in children
ing itraconazole in oral solution compared to capsules. In fact, than in adults, severe infections would probably require higher
itraconazole in oral solution restored the Cmaxs and AUC0–24s doses. In addition, the wide interpatient variations in Cmaxs
to values obtained with an equivalent dose (200 mg) of the and AUC0–24s indicate that plasma itraconazole assays would
capsule preparation in healthy volunteers (7) and thus cor- be required in the treatment of invasive fungal infections.
rected for reduced absorption from capsules in adult neutro- Steady state was reached by about day 11, which is similar to
penic cancer patients. the result reported for adults.
Unlike the case for adults, there is a paucity of pharmaco- In conclusion, itraconazole in oral solution at 5 mg/kg daily
kinetic, tolerability, and safety data on the effects of itracon- for 2 weeks provides potentially therapeutic levels in plasma,
azole in children. In a small pilot study, repeated dosing with which, however, are substantially lower than those obtained at
itraconazole capsules, 50 mg once daily, in seven neutropenic a similar dosage in adult cancer patients. Itraconazole in oral
children aged 3 to 15 years achieved a mean Cmax of 120 ng/ml
after 2 weeks (8). Data from this study were difficult to inter-
pret because itraconazole was not administered on the basis of
body weight. We thus conducted the first systematic repeated-
dose pharmacokinetic study of itraconazole in oral solution in TABLE 3. Adverse events occurring in more than three patients in
infants and children. Immunocompromised patients at high any group
risk for fungal disease were selected because they represent a No of events
substantial proportion of children who may benefit from re-
Age (yr)
ceiving itraconazole, and the pharmacokinetics for this group Adverse event Total
of patients may differ from those for healthy children or those 0.5–2 2–5 5–12
with other underlying diseases, as well as those for healthy or
Oa Rb O R O R O R
immunocompromised adult patients. In addition, itraconazole
in oral solution is potentially useful in children because of Abdominal pain 3 5 4 8 4
difficulties in administration and adjusting dosages on a milli- Diarrhea 1 3 2c 4 8 2
gram-per-kilogram basis with the capsule preparation. Epistaxis 1 3 1 3 2
The results of the present study demonstrate that the phar- Fever 1 3 1 4 2 7 4
macokinetics of itraconazole in oral solution administered to Headache 1 1 5 6 1
Hypertension 3 3 0
children with neoplastic disease differ substantially from those Leg pain 1 3 4 0
in adults with cancer. In the children aged 2 to 12 years, all of Nausea 2 7 2 9 2
whom had neoplastic disease, Cmaxs, Cmins, and AUC0–24s for Pain 1 5 2 6 2
itraconazole were only about a third of those attained for adult Pharyngitis 1 2 3 1 6 1
cancer patients (13, 14) treated with an identical dosage of 5 Rigors 3 2 3 2
mg/kg daily for 14 days. However, the t1/2 of about 30 h in Vomiting 1 5 2 7 2 13 4
children was similar to that reported in adult volunteers (7) a
O, open treatment.
and was not shortened in children, as it is with fluconazole b
R, runout period.
(10). Lower concentrations of itraconazole in plasma in chil- c
Including Clostridium difficile and bloody diarrhea.
408 DE REPENTIGNY ET AL. ANTIMICROB. AGENTS CHEMOTHER.

solution has potential in prophylaxis and treatment of mucosal evaluation of antifungal agents. J. R. Prous Science Publishers, Barcelona,
and invasive fungal infections in children. Spain.
9. Jacqmin, P., A. Van Peer, K. De Beule, P. Stoffels, and J. Heykants. 1995.
Hydroxypropyl-b-cyclodextrin pharmacokinetics and safety in man: a review
ACKNOWLEDGMENTS of the data available until February 1995. In Clinical pharmacokinetics sum-
mary. Janssen Research Foundation, Beerse, Belgium.
This study was supported by a grant from the Janssen Research 10. Lee, J. W., N. L. Seibel, M. Amantea, P. Whitcomb, P. A. Pizzo, and T. J.
Foundation. Walsh. 1992. Safety and pharmacokinetics of fluconazole in children with
We gratefully acknowledge the participation of M. Schroeder, K. neoplastic diseases. J. Pediatr. 120:987–993.
Groen, P. Wallemacq, P. Stoffels, R. Wiels, R. Woestenborghs, A. 11. Persat, F., C. Marzullo, D. Guyotat, M.-J. Rochet, and M. A. Piens. 1992.
Daems, A. Van Peer, J. Heykants, M. Peeters, H. Joosen, and B. Plasma itraconazole concentrations in neutropenic patients after repeated
Banks. We also thank S. Tassé for expert secretarial assistance. high-dose treatment. Eur. J. Cancer 28:838–841.
12. Pizzo, P. A., M. Rubin, A. Freifeld, and T. J. Walsh. 1991. The child with
cancer and infection. II. Nonbacterial infections. J. Pediatr. 119:845–857.
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