Hydroxycarbamide in children with sickle cell anaemia after first-dose vs. chronic therapy: pharmacokinetics and predictive models for drug exposure

Jeremie H. Estepp*, Paweł Wiczling, Joseph Moen, Guolian Kang, Joana Marie Mack, Robert Liem, Julie A. Panepinto, Uttam Garg, Gregory Kearns, Kathleen A. Neville

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Aims: The purposes of this work were to: (1) compare pharmacokinetic (PK) parameters for hydroxycarbamide in children receiving their first dose (HCnew) vs. those receiving chronic therapy (HCchronic), (2) assess the external validity of a published PK dosing strategy, and (3) explore the accuracy of dosing strategies based on a limited number of HC measurements. Methods: Utilizing data from two prospective, multicenter trials of hydroxycarbamide (Pharmacokinetics of Liquid Hydroxyurea in Pediatric Patients with Sickle Cell Anemia; NCT01506544 and Single-Dose (SD) and Steady-State (SS) Pharmacokinetics of Hydroxyurea in Children and Adolescents with Sickle Cell Disease), plasma drug concentration vs. time profiles were evaluated with a model independent approach in the HCnew and HCchronic groups. Various predictive scenarios were analysed to evaluate whether systemic exposure with hydroxycarbamide could be accurately predicted. Results: Absorption of hydroxycarbamide was rapid, variable and dose independent. Dose-normalized peak plasma concentrations and drug exposure (AUC) were higher, and weight-normalized apparent oral clearance was lower in the HCnew group. We assessed a PK-guided dosing strategy along with other predictive scenarios and found that inclusion of plasma samples only slightly improved the accuracy of AUC predictions when compared to a population-based method. Conclusions: Children naïve to hydroxycarbamide exhibit a different PK profile compared to children receiving chronic therapy. Accuracy of population-based dosing is sufficient to target AUCs in individual patients. Further clearance/bioavailability studies are needed to address the factors responsible for variability in the disposition of hydroxycarbamide.

Original languageEnglish (US)
Pages (from-to)1478-1485
Number of pages8
JournalBritish Journal of Clinical Pharmacology
Volume84
Issue number7
DOIs
StatePublished - Jul 1 2018

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Keywords

  • children
  • hydroxycarbamide
  • pharmacokinetics
  • sickle cell disease

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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