Pharmacokinetics and Relative Bioavailability of a Liquid Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia
An open label, 2-arm study of Hydroxyurea (HU) disposition will be conducted in children and adolescents with sickle cell anemia (Hgb SS or Hgb S[MICRO-SYMBOL]0thalassemia) who range in age from 2 to 17 years of age. The general hypotheses to be tested are: 1) that HU pharmacokinetics in children ages [Greater Than] 2 - [Less Than] 5 years who are administered an extemporaneous peroral liquid formulation of the drug previously studied in infants and toddlers (i.e., BABY HUG study) will not differ significantly from those previously reported in older children and adolescents (arm 1, pharmacokinetic study), and 2) that the HU pharmacokinetic profile of the peroral liquid formulation will not differ significantly from the pharmacokinetic profile of Droxia in children and adolescents ages [Greater Than] 5- [Less Than] 17 years of age (arm 2, relative bioavailability study). Hydroxyurea in the liquid formulation has no specific name branding. Hydroxyruea in capsule form is available in generic as well as name brand, Droxia. The FDA has requested the study use Droxia capsules in very specific capsule strengths. Language in this application may reflect this nomenclature.
The study will be an open-label study in a total of 40 pediatric participants with sickle cell anemia (Hgb SS or Hgb S[MICRO-SYMBOL]0thalassemia):
* Pharmacokinetic arm (n[?]16): This will be a single dose study where participants will receive 20mg/kg or the participant's usual dose as a liquid containing hydroxyurea100mg/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.
* Relative bioavailability arm (n[?]24): 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 or the participant's usual daily dose as: 1) a liquid containing 100 mg/mL of hydroxyurea (rounded to the nearest 200mg and no greater than 30 mg/kg), or 2) Droxia 200 mg capsules administered orally.
Venous blood samples will be obtained for determination of study drug concentrations at the following times:
* Pharmacokinetic Study (Arm 1): Predose, then 10 min, 15 min, 30 min, 45 min, and 1, 1.5, 2, 4, 6 and 8 hours post dose. The subset of participants (n[?]6) with steady state sampling will have sampling at Pre-dose, then 10 min, 15 min, 30 min, 45 min, and 1, 1.5, 2, 4, 6 and 8 hours post [Greater Than] 4 consecutive days of dosing and not greater than 13 days.
* Relative Bioavailability Study (Arm 2): Predose, then 10 min, 15 min, 30 min, 45 min, and 1, 1.5, 2, 4, 6, and 8 hours post dose.
* Plasma samples will be assayed for hydroxyurea utilizing good laboratory practice (GLP) validated method and pharmacokinetic parameters determined. For the relative bioavailability arm, the liquid formulation will be considered the test article.
A participant will be eligible for inclusion in this study only if all of the following criteria apply:
For Both Arms:
1. The study participant will be a pediatric (male or female) participant with sickle cell anemia with laboratory (i.e. electrophoretic, chromatographic or DNA) confirmation of the diagnosis of Hemoglobin SS or S[BETA]0thalassemia.
2. Weight >= 10 kg.
3. Participants may or may not be currently receiving hydroxyurea. If participants are taking hydroxyurea, the last dose must be no less than 24 hours prior to the start of the study.
4. Participant is in the
* state (i.e. at least 2 weeks since the last vaso-occlusive crisis, acute chest syndrome episode, or splenic sequestration episode).
5. Clinical evidence of normal gastrointestinal function and structure.
6. No clinical evidence of hepatic compromise including transaminases no more than 3 times the upper limit of normal.
7. A glomerular filtration rate (GFR--estimated from serum creatinine using age-appropriate, validated equations such as the Schwartz equation) > 70 ml/min/1.73m2 and no known renal impairment (creatinine no more than 1.5 times the upper limit of normal for age in the screening laboratory).
8. Body mass index (BMI) >=5th and <= 95th percentile as per CDC growth charts.
9. The parent or guardian is willing and able to provide a signed and dated written informed consent form prior to any study related procedures. When appropriate, the participant has signed an assent to participate according to local IRB guidelines.
10. The participants and/or participant[Single Quote]s parents are able to understand and comply with protocol requirements, instructions, and protocol-stated restrictions such that the participant is likely to complete the study as planned.
11. Based on the opinion of the physicians providing patient care and those conducting the study, there are no apparent contraindications for inclusion as a participant in a pharmacokinetic study.
For the Pharmacokinetic Study (Arm 1):
12. Participant is >= 2 years and <= 5 years of age.
13. The participant is able to consume a minimum of 30 ml of water following ingestion of the study article.
For the Relative Bioavailability Study:
14. Participant is > 5 years and <= 17 years of age.
15. All females of child-bearing potential must be found to have a negative serum pregnancy test prior to initial dosing and be willing to practice appropriate contraceptive measures, including abstinence, from the time of the initial pregnancy testing through the remainder of the study (30 days after last administration of investigational agents).
16. The participant is able to ingest both capsule and liquid study articles and consume a minimum of 30 ml of water following ingestion of medication.