Population pharmacokinetics of hydroxyurea for children and adolescents with sickle cell disease

Paweł Wiczling*, Robert I Liem, Julie A. Panepinto, Uttam Garg, Susan M. Abdel-Rahman, Gregory L. Kearns, Kathleen A. Neville

*Corresponding author for this work

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The objective of this study was to develop a population pharmacokinetic (PK) model sufficient to describe hydroxyurea (HU) concentrations in serum and urine following oral drug administration in pediatric patients with sickle cell disease. Additionally, the measured hydroxyurea concentrations for particular sampling time were correlated with exposure measures (AUC) to find the most predictive relationship. Hydroxyurea concentrations were determined in 21 subjects. Using a population nonlinear mixed-effect modeling, the HU PK was best described by a one-compartment model with two elimination pathways (metabolic and renal) and a transit compartment absorption. The typical mean absorption time was 0.222hour. The typical apparent volume of distribution was 21.8L and the apparent systemic clearance was 6.88L/h for an average weight patient of 30.7kg. The 50% of the HU dose was renally excreted. Linear correlations were apparent between the plasma HU concentration at 1, 1.5, 2, 4, and 6hours post-dose and AUC with the most significant (R2=0.71) observed at 1.5hours. A population PK model was successful in describing HU disposition in plasma and urine. Data from the model also demonstrated that HU plasma concentrations at 1.5hours after an oral dose of the drug were highly predictive of systemic drug exposure.

Original languageEnglish (US)
Pages (from-to)1016-1022
Number of pages7
JournalJournal of Clinical Pharmacology
Volume54
Issue number9
DOIs
StatePublished - Jan 1 2014

Fingerprint

Hydroxyurea
Sickle Cell Anemia
Pharmacokinetics
Population
Area Under Curve
Urine
Metabolic Networks and Pathways
Pharmaceutical Preparations
Oral Administration
Pediatrics
Kidney
Weights and Measures
Serum

Keywords

  • hydroxyurea
  • sickle cell disease
  • therapeutic drug monitoring

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Medicine(all)

Cite this

Wiczling, P., Liem, R. I., Panepinto, J. A., Garg, U., Abdel-Rahman, S. M., Kearns, G. L., & Neville, K. A. (2014). Population pharmacokinetics of hydroxyurea for children and adolescents with sickle cell disease. Journal of Clinical Pharmacology, 54(9), 1016-1022. https://doi.org/10.1002/jcph.303
Wiczling, Paweł ; Liem, Robert I ; Panepinto, Julie A. ; Garg, Uttam ; Abdel-Rahman, Susan M. ; Kearns, Gregory L. ; Neville, Kathleen A. / Population pharmacokinetics of hydroxyurea for children and adolescents with sickle cell disease. In: Journal of Clinical Pharmacology. 2014 ; Vol. 54, No. 9. pp. 1016-1022.
@article{06967e9c3b10479e8bdd51ff59f1655b,
title = "Population pharmacokinetics of hydroxyurea for children and adolescents with sickle cell disease",
abstract = "The objective of this study was to develop a population pharmacokinetic (PK) model sufficient to describe hydroxyurea (HU) concentrations in serum and urine following oral drug administration in pediatric patients with sickle cell disease. Additionally, the measured hydroxyurea concentrations for particular sampling time were correlated with exposure measures (AUC) to find the most predictive relationship. Hydroxyurea concentrations were determined in 21 subjects. Using a population nonlinear mixed-effect modeling, the HU PK was best described by a one-compartment model with two elimination pathways (metabolic and renal) and a transit compartment absorption. The typical mean absorption time was 0.222hour. The typical apparent volume of distribution was 21.8L and the apparent systemic clearance was 6.88L/h for an average weight patient of 30.7kg. The 50{\%} of the HU dose was renally excreted. Linear correlations were apparent between the plasma HU concentration at 1, 1.5, 2, 4, and 6hours post-dose and AUC with the most significant (R2=0.71) observed at 1.5hours. A population PK model was successful in describing HU disposition in plasma and urine. Data from the model also demonstrated that HU plasma concentrations at 1.5hours after an oral dose of the drug were highly predictive of systemic drug exposure.",
keywords = "hydroxyurea, sickle cell disease, therapeutic drug monitoring",
author = "Paweł Wiczling and Liem, {Robert I} and Panepinto, {Julie A.} and Uttam Garg and Abdel-Rahman, {Susan M.} and Kearns, {Gregory L.} and Neville, {Kathleen A.}",
year = "2014",
month = "1",
day = "1",
doi = "10.1002/jcph.303",
language = "English (US)",
volume = "54",
pages = "1016--1022",
journal = "Journal of Clinical Pharmacology",
issn = "0091-2700",
publisher = "SAGE Publications Inc.",
number = "9",

}

Wiczling, P, Liem, RI, Panepinto, JA, Garg, U, Abdel-Rahman, SM, Kearns, GL & Neville, KA 2014, 'Population pharmacokinetics of hydroxyurea for children and adolescents with sickle cell disease', Journal of Clinical Pharmacology, vol. 54, no. 9, pp. 1016-1022. https://doi.org/10.1002/jcph.303

Population pharmacokinetics of hydroxyurea for children and adolescents with sickle cell disease. / Wiczling, Paweł; Liem, Robert I; Panepinto, Julie A.; Garg, Uttam; Abdel-Rahman, Susan M.; Kearns, Gregory L.; Neville, Kathleen A.

In: Journal of Clinical Pharmacology, Vol. 54, No. 9, 01.01.2014, p. 1016-1022.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Population pharmacokinetics of hydroxyurea for children and adolescents with sickle cell disease

AU - Wiczling, Paweł

AU - Liem, Robert I

AU - Panepinto, Julie A.

AU - Garg, Uttam

AU - Abdel-Rahman, Susan M.

AU - Kearns, Gregory L.

AU - Neville, Kathleen A.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - The objective of this study was to develop a population pharmacokinetic (PK) model sufficient to describe hydroxyurea (HU) concentrations in serum and urine following oral drug administration in pediatric patients with sickle cell disease. Additionally, the measured hydroxyurea concentrations for particular sampling time were correlated with exposure measures (AUC) to find the most predictive relationship. Hydroxyurea concentrations were determined in 21 subjects. Using a population nonlinear mixed-effect modeling, the HU PK was best described by a one-compartment model with two elimination pathways (metabolic and renal) and a transit compartment absorption. The typical mean absorption time was 0.222hour. The typical apparent volume of distribution was 21.8L and the apparent systemic clearance was 6.88L/h for an average weight patient of 30.7kg. The 50% of the HU dose was renally excreted. Linear correlations were apparent between the plasma HU concentration at 1, 1.5, 2, 4, and 6hours post-dose and AUC with the most significant (R2=0.71) observed at 1.5hours. A population PK model was successful in describing HU disposition in plasma and urine. Data from the model also demonstrated that HU plasma concentrations at 1.5hours after an oral dose of the drug were highly predictive of systemic drug exposure.

AB - The objective of this study was to develop a population pharmacokinetic (PK) model sufficient to describe hydroxyurea (HU) concentrations in serum and urine following oral drug administration in pediatric patients with sickle cell disease. Additionally, the measured hydroxyurea concentrations for particular sampling time were correlated with exposure measures (AUC) to find the most predictive relationship. Hydroxyurea concentrations were determined in 21 subjects. Using a population nonlinear mixed-effect modeling, the HU PK was best described by a one-compartment model with two elimination pathways (metabolic and renal) and a transit compartment absorption. The typical mean absorption time was 0.222hour. The typical apparent volume of distribution was 21.8L and the apparent systemic clearance was 6.88L/h for an average weight patient of 30.7kg. The 50% of the HU dose was renally excreted. Linear correlations were apparent between the plasma HU concentration at 1, 1.5, 2, 4, and 6hours post-dose and AUC with the most significant (R2=0.71) observed at 1.5hours. A population PK model was successful in describing HU disposition in plasma and urine. Data from the model also demonstrated that HU plasma concentrations at 1.5hours after an oral dose of the drug were highly predictive of systemic drug exposure.

KW - hydroxyurea

KW - sickle cell disease

KW - therapeutic drug monitoring

UR - http://www.scopus.com/inward/record.url?scp=84905510021&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84905510021&partnerID=8YFLogxK

U2 - 10.1002/jcph.303

DO - 10.1002/jcph.303

M3 - Article

C2 - 24729271

AN - SCOPUS:84905510021

VL - 54

SP - 1016

EP - 1022

JO - Journal of Clinical Pharmacology

JF - Journal of Clinical Pharmacology

SN - 0091-2700

IS - 9

ER -