Primary Objective 1. Define the pharmacokinetics of liquid-formulated HU in infants (9 months to \<2 years) 2. Assess the relative bioavailability of HU "sprinkles" compared to capsules in children and adolescents (≥2 to 18 years). Secondary Objective: Compare PK parameters in infants versus older children on this study and those from our previous "Pharmacokinetics and Bioavailability of a Liquid Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia" (NCT01506544) trial. Exploratory Objectives: Capture information regarding the taste of HU sprinkles using palatability questionnaire. This trial is an open label, single center assessment of the pharmacokinetics of two formulations of hydroxyurea (HU) designed to (1) determine the pharmacokinetic profile of a liquid formulation in infants and to (2) determine the bioavailability of "sprinkles", a novel method of administration for older children. The study aims to generate data to facilitate FDA approval for HU in children and potentially validate a new mode of administration ("sprinkles") that will optimize access and adherence for children in the US and globally.
HOPE18 will be an open label, 2-arm study of HU disposition in 48 children with SCD. In Arm 1, n=18 infants ages 9 months to 2 years will be administered an extemporaneous oral liquid formulation of HU on a single occasion followed by PK sampling. The dose administered will be \~20 mg/kg/day or the infant's usual daily dose. In Arm 2, n=30 children who range in age from 2 to 18 years will be administered HU, both a sprinkle formulation and capsules (Droxia® 200 mg), on two separate occasions separated by at least 1 day but no more than 30 days in a randomized, crossover fashion. The doses of HU on each occasion will be rounded to the nearest 200 mg and will not exceed 35 mg/kg or 2000 mg. We hypothesize that the PK profile of the sprinkle formulation will not differ significantly from the PK profile of Droxia® capsules in children and adolescents ages ≥2 - 18 years of age. Participants in both arms will be followed up to 30 days from receiving last HU dose.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
1
Drug: Hydroxyurea oral liquid dose administered will be 20mg/kg/day or infants's usual daily dose.
Drug: Hydroxyurea both a sprinkle formulation and capsules (Droxia 200mg) administered on 2 separate occasions.
St. Jude Children's Research Hospital
Memphis, Tennessee, United States
The Maximum Concentration Observed After Dosing (Cmax) for HU Liquid Formulation in Infants (9 Months to <2 Years)
Summary statistics including mean, standard deviation (SD) will be reported.
Time frame: 1 day
The Time of Maximum Observed Concentration (Cmax) Relative to Time of Dosing for HU Liquid Formulation in Infants (9 Months to <2 Years)
Summary statistics including mean, standard deviation (SD) will be reported.
Time frame: 1 day
AUClast for HU Liquid Formulation in Infants (9 Months to <2 Years)
The area under the concentration-time curve from time of dosing of the drug to the time of the last measurable concentration or when concentrations were Below the Limit of Quantitation (BLQ) were calculated using either the linear (concentration before Cmax) or log trapezoidal rule (concentrations after Cmax). Summary statistics including mean, standard deviation (SD) will be reported.
Time frame: 1 day
AUCinfinity for HU Liquid Formulation in Infants (9 Months to <2 Years)
The AUC extrapolated from the last measured concentration (Clast) to time infinity using the formula AUClast + Clast / λz. Summary statistics including mean, standard deviation (SD) will be reported.
Time frame: 1 day
Mean Residence Time as Generated by WinNonlin (AUMC/AUC) for HU Liquid Formulation in Infants (9 Months to <2 Years)
Summary statistics including mean, standard deviation (SD) will be reported.
Time frame: 1 day
Apparent Clearance Calculated From Dose/ AUCINF for HU Liquid Formulation in Infants (9 Months to <2 Years)
Summary statistics including mean, standard deviation (SD) will be reported.
Time frame: 1 day
Apparent Clearance Normalized for Body Weight (BW) for HU Liquid Formulation in Infants (9 Months to <2 Years)
Summary statistics including mean, standard deviation (SD) will be reported.
Time frame: 1 day
Elimination Slope for HU Liquid Formulation in Infants (9 Months to <2 Years)
The first-order linear slope associated with the terminal (log-linear) portion of the curve and estimated via linear regression of log concentrations vs. time. Summary statistics including mean, standard deviation (SD) will be reported.
Time frame: 1 day
Terminal Elimination Half-life Obtained From: t½ = ln(2)/ λz for HU Liquid Formulation in Infants (9 Months to <2 Years)
Summary statistics including mean, standard deviation (SD) will be reported.
Time frame: 1 day
The Maximum Concentration Observed After Dosing (Cmax) for HU "Sprinkles" Compared to Capsules in Children and Adolescents (≥2 to 18 Years)
Summary statistics including mean and SD will be reported for "sprinkles" and capsules and will be compared using two-sample t-test or Wilcoxon rank sum test depending on the normality of the data at a significance level of 0.05 per study design above. Logarithmic transformation will be applied if data do not follow normal.
Time frame: 2 days
The Time of Maximum Observed Concentration (Cmax) Relative to Time of Dosing for HU "Sprinkles" Compared to Capsules in Children and Adolescents (≥2 to 18 Years)
Summary statistics including mean and SD will be reported for "sprinkles" and capsules and will be compared using two-sample t-test or Wilcoxon rank sum test depending on the normality of the data at a significance level of 0.05 per study design above. Logarithmic transformation will be applied if data do not follow normal.
Time frame: 2 days
AUClast for HU "Sprinkles" Compared to Capsules in Children and Adolescents (≥2 to 18 Years)
The AUC extrapolated from the last measured concentration (Clast) to time infinity using the formula AUClast + Clast / λz. Summary statistics including mean and SD will be reported for "sprinkles" and capsules and will be compared using two-sample t-test or Wilcoxon rank sum test depending on the normality of the data at a significance level of 0.05 per study design above. Logarithmic transformation will be applied if data do not follow normal.
Time frame: 2 days
AUCinfinity for HU "Sprinkles" Compared to Capsules in Children and Adolescents (≥2 to 18 Years)
The AUC extrapolated from the last measured concentration (Clast) to time infinity using the formula AUClast + Clast / λz. Summary statistics including mean and SD will be reported for "sprinkles" and capsules and will be compared using two-sample t-test or Wilcoxon rank sum test depending on the normality of the data at a significance level of 0.05 per study design above. Logarithmic transformation will be applied if data do not follow normal.
Time frame: 2 days
Mean Residence Time as Generated by WinNonlin (AUMC/AUC) for HU "Sprinkles" Compared to Capsules in Children and Adolescents (≥2 to 18 Years)
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Summary statistics including mean and SD will be reported for "sprinkles" and capsules and will be compared using two-sample t-test or Wilcoxon rank sum test depending on the normality of the data at a significance level of 0.05 per study design above. Logarithmic transformation will be applied if data do not follow normal.
Time frame: 2 days
Apparent Clearance Calculated From Dose/ AUCINF for HU "Sprinkles" Compared to Capsules in Children and Adolescents (≥2 to 18 Years)
Summary statistics including mean and SD will be reported for "sprinkles" and capsules and will be compared using two-sample t-test or Wilcoxon rank sum test depending on the normality of the data at a significance level of 0.05 per study design above. Logarithmic transformation will be applied if data do not follow normal.
Time frame: 2 days
Apparent Clearance Normalized for Body Weight (BW) for HU "Sprinkles" Compared to Capsules in Children and Adolescents (≥2 to 18 Years)
Summary statistics including mean and SD will be reported for "sprinkles" and capsules and will be compared using two-sample t-test or Wilcoxon rank sum test depending on the normality of the data at a significance level of 0.05 per study design above. Logarithmic transformation will be applied if data do not follow normal.
Time frame: 2 days
Elimination Slope for HU "Sprinkles" Compared to Capsules in Children and Adolescents (≥2 to 18 Years)
The first-order linear slope associated with the terminal (log-linear) portion of the curve and estimated via linear regression of log concentrations vs. time. Summary statistics including mean and SD will be reported for "sprinkles" and capsules and will be compared using two-sample t-test or Wilcoxon rank sum test depending on the normality of the data at a significance level of 0.05 per study design above. Logarithmic transformation will be applied if data do not follow normal.
Time frame: 2 days
Terminal Elimination Half-life Obtained From: t½ = ln(2)/ λz for HU "Sprinkles" Compared to Capsules in Children and Adolescents (≥2 to 18 Years)
Summary statistics including mean and SD will be reported for "sprinkles" and capsules and will be compared using two-sample t-test or Wilcoxon rank sum test depending on the normality of the data at a significance level of 0.05 per study design above. Logarithmic transformation will be applied if data do not follow normal.
Time frame: 2 days
The Maximum Concentration Observed After Dosing (Cmax) for Infants Versus Older Children
The older children will include children on arm 2 on this study and those from our previous "Pharmacokinetics and Bioavailability of a Liquid Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia" (NCT01506544) trial. Summary statistics will be reported for the infants and older children and will be compared using two sample t-test or Wilcoxon rank sum test depending on the normality of the data. Logarithmic transformation will be applied if data do not follow normal.
Time frame: 2 days
The Time of Maximum Observed Concentration (Cmax) Relative to Time of Dosing for Infants Versus Older Children
The older children will include children on arm 2 on this study and those from our previous "Pharmacokinetics and Bioavailability of a Liquid Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia" (NCT01506544) trial. Summary statistics will be reported for the infants and older children and will be compared using two sample t-test or Wilcoxon rank sum test depending on the normality of the data. Logarithmic transformation will be applied if data do not follow normal.
Time frame: 2 days
AUClast for Infants Versus Older Children
The area under the concentration-time curve from time of dosing of the drug to the time of the last measurable concentration or when concentrations were Below the Limit of Quantitation (BLQ) were calculated using either the linear (concentration before Cmax) or log trapezoidal rule (concentrations after Cmax). The older children will include children on arm 2 on this study and those from our previous "Pharmacokinetics and Bioavailability of a Liquid Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia" (NCT01506544) trial. Summary statistics will be reported for the infants and older children and will be compared using two sample t-test or Wilcoxon rank sum test depending on the normality of the data. Logarithmic transformation will be applied if data do not follow normal.
Time frame: 2 days
AUCinfinity for Infants Versus Older Children
The AUC extrapolated from the last measured concentration (Clast) to time infinity using the formula AUClast + Clast / λz. The older children will include children on arm 2 on this study and those from our previous "Pharmacokinetics and Bioavailability of a Liquid Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia" (NCT01506544) trial. Summary statistics will be reported for the infants and older children and will be compared using two sample t-test or Wilcoxon rank sum test depending on the normality of the data. Logarithmic transformation will be applied if data do not follow normal.
Time frame: 2 days
Mean Residence Time as Generated by WinNonlin (AUMC/AUC) for Infants Versus Older Children
The older children will include children on arm 2 on this study and those from our previous "Pharmacokinetics and Bioavailability of a Liquid Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia" (NCT01506544) trial. Summary statistics will be reported for the infants and older children and will be compared using two sample t-test or Wilcoxon rank sum test depending on the normality of the data. Logarithmic transformation will be applied if data do not follow normal.
Time frame: 2 days
Apparent Clearance Calculated From Dose/ AUCINF for In Infants Versus Older Children
The older children will include children on arm 2 on this study and those from our previous "Pharmacokinetics and Bioavailability of a Liquid Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia" (NCT01506544) trial. Summary statistics will be reported for the infants and older children and will be compared using two sample t-test or Wilcoxon rank sum test depending on the normality of the data. Logarithmic transformation will be applied if data do not follow normal.
Time frame: 2 days
Apparent Clearance Normalized for Body Weight (BW) for Infants Versus Older Children
The older children will include children on arm 2 on this study and those from our previous "Pharmacokinetics and Bioavailability of a Liquid Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia" (NCT01506544) trial. Summary statistics will be reported for the infants and older children and will be compared using two sample t-test or Wilcoxon rank sum test depending on the normality of the data. Logarithmic transformation will be applied if data do not follow normal.
Time frame: 2 days
Elimination Slope for In Infants Versus Older Children
The first-order linear slope associated with the terminal (log-linear) portion of the curve and estimated via linear regression of log concentrations vs. time. The older children will include children on arm 2 on this study and those from our previous "Pharmacokinetics and Bioavailability of a Liquid Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia" (NCT01506544) trial. Summary statistics will be reported for the infants and older children and will be compared using two sample t-test or Wilcoxon rank sum test depending on the normality of the data. Logarithmic transformation will be applied if data do not follow normal.
Time frame: 2 days
Terminal Elimination Half-life Obtained From: t½ = ln(2)/ λz for Infants Versus Older Children
The older children will include children on arm 2 on this study and those from our previous "Pharmacokinetics and Bioavailability of a Liquid Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia" (NCT01506544) trial. Summary statistics will be reported for the infants and older children and will be compared using two sample t-test or Wilcoxon rank sum test depending on the normality of the data. Logarithmic transformation will be applied if data do not follow normal.
Time frame: 2 days