Genetic Variation and Variability in Posaconazole Pharmacokinetics in Children

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.

Study Overview

• Status: Completed
• Conditions: Fungal Infections
• Intervention / Treatment: Drug: 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.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital Kansas City

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Posaconazole Injection; We will give a single dose of intravenous posaconazole and collect blood samples for pharmacokinetics (PK). The study pool will be enriched by selecting participants with known sequence variations. Every effort will be made to balance age and disease state (HSCT vs. non-HSCT).	Drug: Posaconazole; Posaconazole will be given as a one time intravenous (IV) dose. The dose will take ninety (90) minutes to be infused and will be based on weight at the time of the visit.; Other Names: Noxafil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the plasma concentration versus time curve (AUC) of Posaconazole Injection	Posaconazole concentrations in the plasma will be measured after a single dose of posaconazole injection to estimate the area under the concentration-versus-time curve (AUC). Blood samples for the assessment of AUC will be collected predose on Day 1 and then at specified time points up to 96 hours postdose.	Predose on Day 1 up to 96 hours postdose
Maximum Concentration (Cmax) of Posaconazole Injection	Blood samples for the assessment of Cmax will be collected predose on Day 1 and then at prespecified time points up 96 hours postdose.	Predose on Day 1 up to 96 hours postdose
Time of maximum concentration (Tmax)	Blood samples for the assessment of Tmax will be collected predose on Day 1 and then at prespecified time points up to 96 hours postdose.	Predose on Day 1 up to 96 hours postdose
Terminal half-life (t1/2)	Blood samples for the assessment of t1/2 will be collected predose on Day 1 and then at prespecified time points up to 96 hours postdose.	Predose on Day 1 up to 96 hours postdose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Treatment-Emergent Adverse Events (AEs)	AEs are any unfavorable and unintended signs, symptom, or disease temporally associated with the use of a study drug, whether or nor considered related to this study drug. Treatment-emergent AEs are any event not present before starting study drug treatment or any event that was present before treatment that worsened in either intensity or frequency after exposure to study drug.	Up to Day 4
Number of Participants with Treatment-Related AEs	AEs are any unfavorable and unintended signs, symptom, or disease temporally associated with the use of a study drug, whether or nor considered related to this study drug. Treatment-related AEs are considered by the investigator to be related to the study drug.	Up to Day 4

Collaborators and Investigators

• Sponsor: Children's Mercy Hospital Kansas City
• Investigators: Principal Investigator: Dwight E Yin, MD, MPH, Children's Mercy Hospital Kansas City

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2015
• Primary Completion (Actual): December 31, 2018
• Study Completion (Actual): December 31, 2018

Study Registration Dates

• First Submitted: January 29, 2015
• First Submitted That Met QC Criteria: February 3, 2015
• First Posted (Estimate): February 9, 2015

Study Record Updates

• Last Update Posted (Actual): December 22, 2020
• Last Update Submitted That Met QC Criteria: December 18, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: pediatrics; pharmacokinetics; fungi; leukemia; bone marrow failure syndrome; triazoles; transplantation, hematopoietic stem cell
• Additional Relevant MeSH Terms: Infections; Bacterial Infections and Mycoses; Mycoses; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; 14-alpha Demethylase Inhibitors; Trypanocidal Agents; Posaconazole
• Other Study ID Numbers: 1490413

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No