Clinical trial NCT02358499: Genetic Variation and Variability in Posaconazole Pharmacokinetics in Children
Official title: Genetic Variation and Variability in Posaconazole Pharmacokinetics in Children
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Fungal Infections
Keywords: triazoles
fungi
transplantation, hematopoietic stem cell
leukemia
pediatrics
pharmacokinetics
bone marrow failure syndrome
Lead sponsor: Children's Mercy Hospital Kansas City
Sponsor class: OTHER
First posted: 2015-02-09
Enrollment: 31
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief summary: The main goal of this study is to see how the body breaks down an antifungal drug named posaconazole in children with certain cancers, blood disorders, or transplantation of bone marrow or similar blood cells. This study will also help us learn whether a child's age, genetics, or disease affect how well the body breaks down posaconazole.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Area under the plasma concentration versus time curve (AUC) of Posaconazole Injection
timeFrame: Predose on Day 1 up to 96 hours postdose
measure: Maximum Concentration (Cmax) of Posaconazole Injection
timeFrame: Predose on Day 1 up to 96 hours postdose
measure: Time of maximum concentration (Tmax)
timeFrame: Predose on Day 1 up to 96 hours postdose
measure: Terminal half-life (t1/2)
timeFrame: Predose on Day 1 up to 96 hours postdose
Secondary outcomes:
measure: Number of Participants with Treatment-Emergent Adverse Events (AEs)
timeFrame: Up to Day 4
measure: Number of Participants with Treatment-Related AEs
timeFrame: Up to Day 4
Other outcomes:
Locations:
city: Kansas City
country: United States
facility: Children's Mercy Hospital Kansas City
state: Missouri
Study officials:
affiliation: Children's Mercy Hospital Kansas City
name: Dwight E Yin, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References: