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

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.

Keywords: children; hydroxycarbamide; pharmacokinetics; sickle cell disease.

© 2017 The British Pharmacological Society.

Figures

Figure 1

(A) Mean hydroxycarbamide (HC) (μg ml−1) and (B) dose‐normalized HC concentration (μg ml−1 per 1 mg kg−1 HU) per time (h) profiles in children on chronic HC therapy (HCchronic) and children who are receiving the first dose of drug (HCnew). Error bars represent standard deviation of the mean

Figure 2

(A) Coefficient of determination (R2) of the linear correlation between HC concentration and observed AUCinf at different single sampling time points in 59 children. Plasma hydroxycarbamide (HC) concentrations have a positive relationship with AUCinf beginning 1.5 h after the initial dosage (P < 0.0001; Pearson) which is maintained until the eighth hour. (B) Scatterplot of a selected relationship between a single measured plasma HC level in 59 children at 4.0 h post HC ingestion and the observed AUCinf (Supplemental Figure S1)

Figure 3

Boxplot summarizing the distribution of AUCinf prediction errors for five tested scenarios. Closed symbols represent naïve participants whereas open symbols represent chronically treated participants. Scenario 1 is based on the equation: 3.48*C1.5hr + 24.3 using a single plasma hydroxycarbamide (HC) measurement obtained 1.5 h after ingestion. Scenario 2 is a previously published population prediction model 9 with no sampling. Scenario 3 is a MAP‐Bayesian prediction based on a single plasma HC measurement at 1.5 h after ingestion. Scenario 4 is a previously reported MAP‐Bayesian prediction based on three plasma HC measurements (15–20 min, 50–60 min, and 3 h) 10. Scenario 5 is a MAP‐Bayesian predictions based on 12 plasma measurements