This study will examine how children's bodies metabolize and eliminate the anti-fungal drug
voriconazole. The results will yield information needed to make recommendations for safe
and effective dosing of the drug in children. Children with reduced immune function-such as
those receiving drugs for cancer treatment-are at high risk for serious fungal infections.
Children between 2 and 12 years old who need treatment to prevent fungal infections may be
eligible for this study. Candidates will be screened with a physical examination, eye
examination, and blood and urine tests.
Children in the study will be hospitalized for 21 days. They will receive voriconazole
twice a day (every 12 hours) for 8 days, infused through a vein over a period of 1 to 2
hours. The dose will be determined based on the individual child's weight. Blood samples
will be collected at various intervals before and after the infusions on days 1, 2, 4 and 8
to determine the amount of drug in the blood. On day 8, the child will have another
physical and eye examination, as well as additional blood and urine tests. If additional
treatment is required, voriconazole may be continued for up to day 21. (Children who
require the drug for more than 21 days may receive it under another research protocol.) On
the last day of treatment, the child will have another physical examination, and blood and
urine tests. These procedures will be repeated again at 30 to 35 days following the last
dose of drug. A small sample of blood will also be analyzed for genetic information related
to the rate of metabolism of voriconazole-that is, how fast or slow it is cleared
(eliminated) by the liver.
Voriconazole is effective against several different fungi. It may protect children against
serious fungal infections with fewer side effects than standard available therapy.
The objective of this study is to evaluate the serum levels and pharmacokinetic parameters
achieved following two dosage levels of voriconazole. In addition, the safety and
toleration of intravenous voriconazole at two dosage levels in an immunocompromised
pediatric patient population will be evaluated. Also, the plasma concentrations of the
major metabolite of voriconazole (N-oxide) in these patients will be performed. The study
is designed as a multi-center, open label multi-dose study of intravenous voriconazole.
Intravenous voriconazole will be administered prophylactically twice daily to
immunocompromised children at high risk for invasive mycoses. The patient population
consists of children ages 2 years to 12 years of age; two age groups will be studied (2-<6,
6-12). Initial dosage levels will be 3mg/kg q12h and 4mg/kg q12h. The planned sample size
is 24 children. For those children who do not complete the full 8 days of kinetics, a
replacement patient will be added. Immunocompromised children at high risk for invasive
mycoses will receive voriconazole prophylactically. Therapy will be initiated within 48
hours after completion of chemotherapy. Voriconazole therapy will continue until recovery
from neutropenia. The first 12 children will initially receive a loading dose of 6mg/kg X 2
doses followed by 3mg/kg BID through day 4 of therapy. Twelve hour pharmacokinetics will be
collected on day 4. Children will then receive 4mg/kg starting on the second dose of day 4
and will continue at that dosage level until recovery from neutropenia. Kinetics will again
be collected at the 4mg/kg dosage level on day 8 of therapy. If the mean peak plasma
concentration of voriconazole in the first 12 patients following 4mg/kg q12h dosing is less
than 4,000ng/ml., the remaining 12 patients will receive voriconazole after day 4 at a
dosage of 5mg/kg.
Children (male or female) ages 2-12 years who require treatment for the prevention of
systemic fungal infection.
Children who are expected to develop neutropenia lasting for more than 10 days following
chemotherapy for one of the following conditions: leukemia, lymphoma, aplastic anemia, or
as the preparative regimen for bone marrow transplantation.
Patients who are anticipated to live more than 3 months.
Females of child-bearing potential (post-menarchal) must have a negative pregnancy test at
Informed consent of the parent or legally authorized representative obtained prior to
Assent will be obtained from minors capable of understanding.
No patients who are receiving and cannot discontinue the following drugs at least 24 hours
prior to study start: terfenadine and cisapride (due to the possibility of QTc
prolongation). Omegprazole (an inhibitor of CYP2C19) which is known to increase plasma
No patients who have received the following drugs within 14 days prior to study entry:
rifampicin, rifabutin, carbamazepine, phenytoin, nevirapine and barbiturates as these are
potent inducers of hepatic enzymes and will result in undetectable levels of voriconazole.
No patients who have received astemizole within the previous 60 days.
No patients who are taking or are likely to receive any investigational drugs except:
used for cancer treatment, antiretroviral agents, and drugs used for treatments of any
AIDS defining opportunistic infections.
No patients with a history or hypersensitivity to or severe intolerance of azole
No patients who have already been entered onto this protocol once.
No patient with medical history or evidence of cardiac arrhythmia.
No patients with AST and ALT greater than or equal to 5XULN.
No patients with moderate and severe renal impairment (i.e., calculated creatine clearance
less than 30ml/min). If creatinine clearance is reduced to less than 30 ml/min at any
time during the study, the patient must be discontinued from the study. Creatine
clearance will be calculated using the following equation: 0.55 X height (cm)/serum
Any other condition which, in the opinion of the investigator, would make the patient
unsuitable for enrollment.