Genetic Variation and Variability in Posaconazole Pharmacokinetics in Children

The purpose of this research study is to see how the body breaks down posaconazole, which has
limited data in children. Posaconazole injection has been approved by the FDA for prevention
or treatment of certain fungal infections in adult patients. In children, however, we don't
have data on how best to give posaconazole or whether the dosing should be personalized to
individual children. This study aims to determine pharmacokinetics of posaconazole aqueous
solution for injection in children aged 2 through 17 years and explores differences in drug
exposure by age, genetics, and disease state. Children will receive a single dose of
posaconazole injection and have their blood levels of posaconazole checked. The study will
also check for safety after giving the posaconazole.

Inclusion Criteria:

1. Age 2 years to under 18 years

2. Weight ≥10 kg

3. Diagnosis of any of the following: any malignancy (e.g., acute myelogenous leukemia
[AML], acute lymphoblastic leukemia [ALL], lymphoma, solid tumor malignancy),
hemophagocytic syndrome, bone marrow failure syndrome (e.g., myelodysplastic syndrome
and aplastic anemia), hematopoietic stem cell transplantation (HSCT) recipient, or
primary immune deficiency with a neutrophil or T-cell defect (e.g., chronic
granulomatous disease, hyper IgE syndrome, severe combined immune deficiency).

Exclusion Criteria:

1. A female subject must not be pregnant, intend to become pregnant during the study, or
breastfeed

2. A subject must not be receiving any of the following medications within 24 hours
before or after posaconazole infusion (or according to standard of care protocols):
sirolimus, everolimus, pimozide, quinine, HMG-CoA reductase inhibitors primarily
metabolized through CYP3A4 (e.g., atorvastatin, lovastatin, simvastatin), ergot
alkaloids (ergotamine, dihydroergotamine), methadone, astemizole, cisapride,
halofantrine, salmeterol, or vincristine. Potential enrollees will be screened for
additional concomitant medications that pose serious safety concerns when given
concomitantly to posaconazole. Any of these medications will be an exclusion
criterion, unless the concomitant medications may be held for 24 hours before and
after posaconazole infusion or according to standard of care protocols

3. A subject must not be receiving any of the following medications concomitant (within 5
half-lives prior) to posaconazole infusion or PK sampling: rifampin, rifapentine,
rifabutin, phenytoin, efavirenz, fosamprenavir, or cimetidine. Potential enrollees
will be screened for additional concomitant medications that may affect posaconazole
metabolism. Any of these medications will be an exclusion criterion, unless the
concomitant medications may be held for 5 half-lives prior to posaconazole infusion
and through PK sampling

4. A subject must not have moderate or severe liver dysfunction (except in chronic cases
as judged by the P.I.) at Baseline, defined as:

- A subject must not have moderate or severe liver dysfunction at Baseline, defined
as: Aspartate aminotransferase (AST) > 5 times the upper limit of normal (ULN),
OR

- Alanine aminotransferase (ALT) > 5 times the ULN, OR

- Serum total bilirubin >2.5 times the ULN, OR

5. A subject must not have an electrocardiogram (ECG) with prolonged age, sex-adjusted
QTc interval.

6. A subject must not have a history of dysrhythmia.

7. A subject must not have creatinine clearance levels (measured or calculated) below 50
mL/min/1.73 m2.

8. A subject must not have a history of Type 1 hypersensitivity or idiosyncratic
reactions to azole agents.