Hydroxycarbamide in Children with Sickle Cell Anemia After First-dose Vs. Chronic Therapy: Pharmacokinetics and Predictive Models for Drug Exposure

Abstract

Aims

The purpose of this work was to (1) compare pharmacokinetic (PK) parameters for hydroxycarbamide in children receiving their first dose (HC_new) versus those receiving chronic therapy (HC_chronic), (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 versus time profiles were evaluated with a model independent approach in the HC_new and HC_chronic groups. Various predictive senerios were analyzed to evaluate if 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_new 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.

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