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Hydroxycarbamide in children with sickle cell anaemia after first-dose vs. chronic therapy: pharmacokinetics and predictive models for drug exposure. Br J Clin Pharmacol 2018 07;84(7):1478-1485

Date

09/09/2017

Pubmed ID

28884840

Pubmed Central ID

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 (HC ) vs. those receiving chronic therapy (HC ), (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 HC and HC 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 HC 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.

Author List

Estepp JH, Wiczling P, Moen J, Kang G, Mack JM, Liem R, Panepinto JA, Garg U, Kearns G, Neville KA

Author

Julie A. Panepinto MD, MSPH Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adolescent
Anemia, Sickle Cell
Antisickling Agents
Area Under Curve
Biological Availability
Child
Child, Preschool
Dose-Response Relationship, Drug
Drug Administration Schedule
Female
Humans
Hydroxyurea
Male
Models, Biological
Prospective Studies
jenkins-FCD Prod-387 b0ced2662056320369de4e5cd5f21c218c03feb3