Pharmacokinetics (PK) of Liquid Hydroxyurea in Pediatric Patients With Sickle Cell Anemia

NCT01506544 | Completed Phase 1 DMC

• 2 other identifiers: Hydroxyurea PharmacokeneticHHSN275201000003I
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 6

Brief Summary

Hydroxyurea (HU) is approved by the United States Food and Drug Administration (FDA) to treat adults with sickle cell anemia. Hydroxyurea has also been tested and used with children with sickle cell anemia. However, there are not many studies describing the disposition of drug in children less than 5 years old. The FDA has requested this study to better understand how children ages 2 to 17 years with sickle anemia absorb and eliminate the drug (this is called pharmacokinetics). The investigators will measure how much Hydroxyurea (HU) gets into the bloodstream at different time points after taking this medication.

Conditions

Sickle Cell Anemia

Keywords

HU; Hydroxyurea; Sickle cell; Pediatric

Outcome Measures

Primary Outcomes (2)

• Composite of Pharmacokinetics

  Cmax, Area Under Curve, Tmax. Also, the following pharmacokinetic parameters will be derived for each participant using standard techniques: Apparent absorption rate constant, Apparent terminal elimination rate constant, Apparent steady state volume of distribution, Apparent plasma clearance. A compartment, model-based, classical fitting paradigm of the plasma concentration vs. time data will be applied to each subjects' data. Standard goodness of fit criteria will be employed. Subjects aged greater than or equal to 2 and less than or equal to 17 years.

  predose, 0.17, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12 hours post-dose

• Pharmacokinetics of HU

  To evaluate the relative bioavailability of a liquid HU formulation (100mg/mL0 in participants ages greater that 5 and less than or equal to 17 years of age compared to standard therapy utilizing Droxia 200mg capsules

  predose, 0.17, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12 hours post-dose

Secondary Outcomes (1)

• Bioavailability of HU

  predose, 0.17, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8 hours post-dose

Study Arms (2)

Arm 1 Pharmacokinetic study

EXPERIMENTAL

This will be a single dose study where participants will receive 20mg/kg or the participant's usual dose as a liquid containing hydroxyurea 100mg/mL. For a subset of participants (n= at least 6), a multiple-dose, steady state (i.e. at least 4 consecutive days of dosing) study will be performed.

Drug: Hydroxyurea

Arm 2: Relative bioavailability study

ACTIVE COMPARATOR

This will be a single dose study. Participants will receive each of the two following treatments of HU in a randomized, crossover fashion: Either approximately 20 mg/kg/day (rounded to the nearest 200mg and no greater than 30 mg/kg) or the participant's usual daily dose as: 1) a liquid containing 100 mg/mL of hydroxyurea, or 2) Droxia® 200 mg capsules administered orally.

Drug: Hydroxyurea

Interventions

Hydroxyurea DRUG

20mg/kg of Hydroxyurea or the patient's standard daily dose

Also known as: Droxia Capsules, Hydrea

Arm 1 Pharmacokinetic study; Arm 2: Relative bioavailability study

Eligibility Criteria

• Age: 2 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may not qualify if:

• Chronic transfusion therapy, or transfused within 3 months of study participation.
• Known renal impairment (creatinine greater than 1.5 times the upper limit of normal for age in the screening laboratory).
• Known hepatic impairment or elevated transaminases (greater than 3 times normal).
• Known presence of malignancy.
• The participant is unwilling and/or unable to abstain from use of tobacco- or nicotine-containing products for 24 hours prior to screening and for 24 hours prior to dosing until collection of the final PK sample during each treatment period.
• Diagnoses other than sickle cell anemia or sickle beta-zero thalassemia (i.e., other sickle cell variants or sickle hereditary persistence of fetal hemoglobin).
• Blood count parameters as follows: Hemoglobin less than 6.0 gm/dL, absolute reticulocyte count less than 80,000 mm-3, neutrophil count less than 1200 mm-3, platelet count less than 150,000 mm-3.
• The participant has used opiates, H2 blockers, proton pump inhibitors, antacids, other GI motility agents or any other medication that, in the opinion of the investigator and/or sponsor, will interfere with the study procedures or affect the interpretation of the results of the study for 3 days prior to the first dose of study.
• Use of over the counter non-steroidal anti-inflammatory agent or narcotic analgesic within 3 days.
• Participant has received an investigational drug within the past 30 days.
• Use of any illicit or illegal substances.
• The parent or guardian is unwilling or unable to provide a signed and dated written informed consent form prior to any study related procedures, or, when appropriate, the participant has refused to sign an assent to participate according to local IRB guidelines.
• Any other condition or chronic illness, which in the opinion of the Principal Investigator makes participation unadvised or unsafe.
• The caregiver is unwilling or unable to provide a completed study diary for a participant in the steady-state subset.

Sponsors & Collaborators

• Children's Mercy Hospital Kansas City: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (6)

Children's Hospital of Alabama

Birmingham, Alabama, 35233, United States

Location

Children's Memorial Hospital (Northwestern University)

Chicago, Illinois, 60614-3363, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

UT Southwestern University Hospital

Dallas, Texas, 75390-9063, United States

Location

Children's Hospital of Wisconsin

Wauwatosa, Wisconsin, 53226, United States

Location

Related Publications (1)

• Estepp JH, Wiczling P, Moen J, Kang G, Mack JM, Liem R, Panepinto JA, Garg U, Kearns G, Neville KA. Hydroxycarbamide in children with sickle cell anaemia after first-dose vs. chronic therapy: pharmacokinetics and predictive models for drug exposure. Br J Clin Pharmacol. 2018 Jul;84(7):1478-1485. doi: 10.1111/bcp.13426. Epub 2017 Nov 28.

  PMID: 28884840 DERIVED

MeSH Terms

Conditions

Anemia, Sickle Cell

Interventions

Hydroxyurea

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Urea; Amides; Organic Chemicals

Study Officials

• Kathleen Neville, MD, MS

  Children's Mercy Hosptials and Clinics

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Pediatrics

Study Record Dates

• First Submitted: September 30, 2011
• First Posted: January 10, 2012
• Study Start: December 1, 2011
• Primary Completion: December 1, 2013
• Study Completion: January 1, 2014
• Last Updated: December 12, 2014

Record last verified: 2014-12

Locations

US (6)