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Antimicrobial Agents and Chemotherapy, February 1998, p. 404-408, Vol. 42, No. 2
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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
 |
ABSTRACT |
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 ± standard deviation) 571 ± 416 ng/ml, 6,930 ± 5,830 ng · h/ml, and 47 ± 55 h
in the children aged 6 months to 2 years; 534 ± 431 ng/ml,
7,330 ± 5,420 ng · h/ml, and 30.6 ± 25.3 h in
the children aged 2 to 5 years; and 631 ± 358 ng/ml, 8,770 ± 5,050 ng · h/ml, and 28.3 ± 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-
-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.
| |
INTRODUCTION |
Invasive fungal infections are a
growing cause of morbidity and mortality in infants and children with
hematological malignancies or undergoing liver transplantation
(12, 19). These infections are most frequently caused by
Candida or Aspergillus species (12, 19). Unfortunately, treatment of these invasive mycoses is
complicated by problems in diagnosis (4, 19) and the limited
efficacy and toxicities of available systemic antifungal agents
(19). Itraconazole is an orally active triazole antifungal
agent with a wide spectrum of activity and pronounced lipophilic
properties (17, 18). The pharmacokinetics of itraconazole in
healthy adult volunteers are characterized by good oral absorption, an extensive tissue distribution with concentrations in tissue
considerably higher than in plasma, a relatively long elimination
half-life (t1/2) (about 1 day), and
biotransformation into a large number of metabolites (7, 8,
16). Itraconazole is thus potentially useful in the prophylaxis
or treatment of invasive candidiasis or aspergillosis in
immunocompromised children. However, the available capsule formulation
of itraconazole may be difficult to administer to infants and children.
Recently, a 10-mg/ml oral solution of itraconazole was developed, with
hydroxypropyl--cyclodextrin as a solubilizer. With a dosage of 5 mg/kg of body weight once daily, maximum concentrations in serum of
itraconazole exceeded 250 ng/ml in adult patients during autologous
bone marrow transplantation (13) or during remission
induction for acute myeloblastic leukemia (14). These
concentrations of itraconazole in serum were judged to be suitable for
antifungal prophylaxis because of data suggesting an excess of episodes
of invasive pulmonary aspergillosis in patients whose maximum
concentrations of the drug in serum were less than 250 ng/ml
(1). However, pharmacokinetic data on itraconazole in
children are limited, and questions with regard to dosage schedules in
prevention and treatment of systemic fungal infections often arise. The
objective of the present study was to assess the pharmacokinetics of
itraconazole and its active metabolite hydroxyitraconazole during and
after repeated dosing of itraconazole in oral solution, 5 mg/kg per day
for 2 weeks, in infants and children requiring systemic antifungal
prophylaxis or treatment.
| |
MATERIALS AND METHODS |
Patients.
Male and female children aged 6 months to 12 years
with a documented mucosal fungal infection or at risk for the
development of invasive fungal disease were eligible for this study.
Their hospitalization was planned for at least 14 days after the first itraconazole dose. The protocol was approved by the ethics committee of
each participating center, and written informed consent was obtained
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, phenytoin, phenobarbital, carbamazepine, terfenadine, astemizole, warfarin, rifabutin, cisapride, or loratadine concomitantly or in the 2 weeks prior to start of the itraconazole treatment; a known
sensitivity to the azole groups of antifungals; signs of hepatic
dysfunction defined by liver function test results greater than three
times the laboratory's normal ranges, unless etiologically well
documented in cases of liver transplantation; and participation in an
investigational drug trial, except for chemotherapy and growth factor
trials, within 30 days prior to the start of the trial.
Drug administration.
Patients were treated with itraconazole
at dosages of 5 mg/kg once daily for 14 days, provided in an oral
solution containing 10 mg of itraconazole per ml and 400 mg of
hydroxypropyl--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 × g within
2 h. Plasma was stored at 
20°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 hydroxyitraconazole, 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--cyclodextrin. Urine volume and pH were recorded, and
a 20-ml sample was stored at 20°C before analysis.
Hydroxypropyl--cyclodextrin was measured by size exclusion
chromatography with postcolumn complexation (15). The limit
of detection was 1 µg/ml, and the coefficients of variation were 6.3, 4.5, 2.9, and 10.8% at concentrations of 3, 30, 150, and 300 µg/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 itraconazole 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 summation (6); metabolic ratio, calculated as the
AUC0-24 for hydroxyitraconazole divided by the
AUC0-24 for itraconazole (ratiomet);
accumulation factor, calculated 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--cyclodextrin excreted in the urine was calculated by
multiplying the concentration in urine by the volume of urine.
| |
RESULTS |
Twenty-six patients were recruited, of whom eight were between 6 months and 2 years old, seven were 2 to 5 years old, and 11 were 5 to
12 years old. During the open treatment period, three patients in the
group of those aged 5 to 12 years dropped out. Two patients with acute
lymphoblastic leukemia and neuroblastoma, respectively, withdrew on
days 10 and 7 because of fever, which was considered a prophylactic
endpoint, and were given intravenous amphotericin B. A third patient,
with acute lymphoblastic leukemia, dropped out on day 6 because of lack
of cooperation in taking the medication. In addition, one patient with
acute lymphoblastic leukemia in the same age group discontinued taking
the medication because of vomiting on day 11 only but continued to have
assessments. During the run-out period, one patient in the group of
those aged 6 months to 2 years dropped out due to an intercurrent event
(the patient moved). The demographic characteristics and diagnoses of
the patients are summarized in Table 1.
The most frequent intercurrent illness was acute lymphoblastic
leukemia, except in the patients aged between 6 months and 2 years, of
whom six were liver transplant recipients. All patients were
neutropenic, except those who underwent a liver transplantation.
The time courses of the mean concentrations of itraconazole and
hydroxyitraconazole in plasma are shown in Fig.
1. The pharmacokinetic parameters of
itraconazole and hydroxyitraconazole are summarized in Table
2. On day 1, the mean
Cmaxs and AUC0-24s
of itraconazole and hydroxyitraconazole were lower for the group of
those aged 6 months to 2 years than for the other two groups but were
comparable on day 14. The same pattern was observed for the mean
ratiomet. The Tmaxs were comparable
in the three age groups and did not change significantly during
repeated doses. The mean AUC0-24-based accumulation factor
of itraconazole and hydroxyitraconazole from day 1 to 14 ranged from
3.3 to 8.6 and 2.3 to 11.4, respectively. There was a tendency to have
more frequent low Cmins for both itraconazole
and hydroxyitraconazole in the group of those aged 6 months to 2 years.
The t1/2term values measured at steady state were comparable in the three age groups for both itraconazole and
hydroxyitraconazole.
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|
FIG. 1.
Semilogarithmic plot of the mean concentrations in
plasma of itraconazole and hydroxyitraconazole as a function of time
after oral administration of itraconazole in oral solution, 5 mg/kg/day, for 2 weeks to children.
|
|
In the majority of patients (11 of 14), less than 1% of the
hydroxypropyl--cyclodextrin dose was excreted in the urine on days 1 and/or 14. In the other three patients (one in the group of those aged
2 to 5 years and two in the group of those aged 5 to 12 years), the
percentage of the hydroxypropyl--cyclodextrin dose excreted in the
urine did not exceed 11.8%. Given that after intravenous
administration 80 to 90% of the dose is excreted unchanged in the
urine (9), the mean oral bioavailability of
hydroxypropyl--cyclodextrin in the majority of the patients can be
estimated to be less than 1%.
During the open treatment period, adverse events
mainly
gastrointestinal system and general disorderswere reported for all patients, except for two in the group of those aged 6 months to 2 years. The most frequent adverse event was vomiting, which is also
reported for adult cancer patients treated with itraconazole in oral
solution (13, 14). During the run-out period, adverse events
occurred in two patients in the group of those aged 6 months to 2 years, five occurred in the group of those aged 2 to 5 years, and six
occurred in the group of those aged 5 to 12 years. Adverse events
occurring in at least three patients in any group are shown in Table
3. The incidence of adverse events was
higher in patients aged 5 to 12 years. No treatment-related severe or
serious adverse events occurred. All patients showed abnormal
laboratory data at some time during treatment but no consistent,
clinically relevant changes were observed. In the group of those aged 6 months to 2 years, high values for alanine aminotransferase, aspartate
aminotransferase, and gamma-glutamyl transferase were observed in three
liver transplant patients but were considered normal at that stage
after transplantation. Increases in these parameters were also noted in
two patients with acute lymphoblastic leukemia in the group of those
aged 2 to 5 years but were attributed to antineoplastic chemotherapy. Finally, a borderline increase in alanine aminotransferase in a patient
with acute lymphoblastic leukemia in the group of those aged 5 to 12 years was considered to be possibly related to itraconazole.
| |
DISCUSSION |
Itraconazole has a broader spectrum of activity than the other
azoles and is the only commercially available antifungal in this class
with in vitro activity against Aspergillus. Clinical efficacy of itraconazole has been shown in adult patients with candidal
thrush or esophagitis (5) and inferred in patients with
invasive aspergillosis (3). It is thus potentially useful in
the prophylaxis and treatment of mucosal and invasive fungal infections
in children. This first pharmacokinetic study of itraconazole oral
solution in children was prompted by potential differences between
children and adults, as illustrated by the shorter
t1/2 of fluconazole in serum in children with
neoplastic diseases than in adults (10).
The pharmacokinetics of the itraconazole capsule preparation have been
well defined in healthy adult volunteers and immunocompromised patients. In healthy volunteers, intake of the capsules after a meal
enhanced bioavailability (8). In different studies, oral
dosing of 100 mg once daily for 2 weeks produced mean
Cmaxs of 378 and 672 ng/ml,
AUC0-24s of 5,330 and 9,416 ng · h/ml, a
t1/2 of 34 h, and a
Tmax of 3 h (7, 8, 16), but wide intersubject variations were observed. Steady state was attained in 10 to 14 days, and oral bioavailability was disproportionately augmented
by increasing the dose. Much lower itraconazole concentrations were
attained in patients with acute leukemia or autologous bone marrow
transplantation than in healthy volunteers (2, 11). In one
study (2), repeated doses of 200 mg of the itraconazole capsule preparation once daily for 2 weeks produced a mean
Cmax of 412 ng/ml and an AUC0-24 of
6,040 ng · h/ml, compared to 1,028 ng/ml and 15,400 ng · h/ml in healthy adult volunteers (7). Capsules are thus
poorly absorbed in neutropenic cancer patients at greatest risk of
fungal disease. Accordingly, an oral solution of 10 mg of itraconazole
per ml and 400 mg of hydroxypropyl--cyclodextrin per ml which
improves bioavailability by as much as 30% when administered to
healthy volunteers (data on file; Janssen Research Foundation) was
developed. In contrast to the capsule formulation, itraconazole in oral
solution does not need to be administered with food (data on file;
Janssen Research Foundation), and Tmax is
attained more rapidly (8). Repeated-dose pharmacokinetics of
itraconazole in oral solution, 5 mg/kg daily, were essentially
identical in adult autologous bone marrow transplant recipients
(13) and patients receiving chemotherapy for acute myeloid
leukemia (14). After 2 weeks, mean
Cmaxs were 1,464 and 1,486 ng/ml, and mean AUC0-24s were 24,476 and 22,710 ng · h/ml,
respectively, for these two groups of patients. Achievable
concentrations in serum were thus considerably improved in adult
neutropenic cancer patients receiving itraconazole in oral solution
compared to capsules. In fact, itraconazole in oral solution restored
the Cmaxs and AUC0-24s to values
obtained with an equivalent dose (200 mg) of the capsule preparation in
healthy volunteers (7) and thus corrected for reduced
absorption from capsules in adult neutropenic cancer patients.
Unlike the case for adults, there is a paucity of pharmacokinetic,
tolerability, and safety data on the effects of itraconazole in
children. In a small pilot study, repeated dosing with itraconazole capsules, 50 mg once daily, in seven neutropenic 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 interpret
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 infants and children. Immunocompromised patients at high risk for fungal disease were selected because they represent a substantial proportion of children who may benefit from receiving itraconazole, and the pharmacokinetics for this group of patients may differ from those for healthy children or those with other underlying diseases, as well as those for healthy
or immunocompromised adult patients. In addition, itraconazole in oral
solution is potentially useful in children because of difficulties in
administration and adjusting dosages on a milligram-per-kilogram basis
with the capsule preparation.
The results of the present study demonstrate that the pharmacokinetics
of itraconazole in oral solution administered to children with
neoplastic disease differ substantially from those in adults with
cancer. In the children aged 2 to 12 years, all of whom had neoplastic
disease, Cmaxs, Cmins,
and AUC0-24s for itraconazole were only about a third of
those attained for adult cancer patients (13, 14) treated
with an identical dosage of 5 mg/kg daily for 14 days. However, the
t1/2 of about 30 h in children was similar to that reported in adult volunteers (7) and was not
shortened in children, as it is with fluconazole (10). Lower
concentrations of itraconazole in plasma in children with neoplastic
disease than in adults most likely resulted from decreased absorption from the gastrointestinal tract, because of either mucositis or vomiting. The relative contributions of age and underlying disease to
the observed lower levels in the patients aged 2 to 12 years than in
adults cannot be determined from the present study and will require
pharmacokinetic data in healthy volunteers from this same age group.
However, children with neoplastic disease may require higher doses on a
milligram-per-kilogram basis than adults for equivalent prophylactic
and therapeutic benefits. Because the pharmacokinetics of itraconazole
are related nonlinearly to dose, it would be worthwhile to investigate
the pharmacokinetics at higher doses in defined populations of
immunocompromised children. It would be difficult to unequivocally
state that the itraconazole levels obtained at 5 mg/kg daily in this
study are therapeutic, since correlations between levels and outcome
are sparse (1). However, since lower levels are achieved in
children than in adults, severe infections would probably require
higher doses. In addition, the wide interpatient variations in
Cmaxs and AUC0-24s indicate that
plasma itraconazole assays would be required in the treatment of
invasive fungal infections. Steady state was reached by about day 11, which is similar to the result reported for adults.
In conclusion, itraconazole in oral solution at 5 mg/kg daily for 2 weeks provides potentially therapeutic levels in plasma, which,
however, are substantially lower than those obtained at a similar
dosage in adult cancer patients. Itraconazole in oral solution has
potential in prophylaxis and treatment of mucosal and invasive fungal
infections in children.
| |
ACKNOWLEDGMENTS |
This study was supported by a grant from the Janssen Research
Foundation.
We gratefully acknowledge the participation of M. Schroeder, K. Groen,
P. Wallemacq, P. Stoffels, R. Wiels, R. Woestenborghs, A. Daems, A. Van
Peer, J. Heykants, M. Peeters, H. Joosen, and B. Banks. We also thank
S. Tassé for expert secretarial assistance.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Microbiology and Immunology, Sainte-Justine Hospital and University of Montreal, 3175 Côte Sainte-Catherine, Montreal, Quebec, Canada H3T 1C5. Phone: (514) 345-4643. Fax: (514) 345-4860. E-mail:
louisr{at}globale.net.
| |
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Antimicrobial Agents and Chemotherapy, February 1998, p. 404-408, Vol. 42, No. 2
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
