Title

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

Document Type

Article

Publication Date

7-1-2018

Identifier

PMCID: PMC6005595; DOI: 10.1111/bcp.13426

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.

Journal Title

British journal of clinical pharmacology

Volume

84

Issue

7

First Page

1478

Last Page

1485

MeSH Keywords

Anemia, Sickle Cell; Hydroxyurea/pharmacokinetics; Child

Keywords

Hydroxycarbomide; Sickle cell anemia

Share

COinS