3 years ago

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

Gregory Kearns, Robert Liem, Paweł Wiczling, Uttam Garg, Julie A. Panepinto, Joseph Moen, Jeremie H. Estepp, Joana Marie Mack, Kathleen A. Neville, Guolian Kang
Aims The purpose of this work was to (1) compare pharmacokinetic (PK) parameters for hydroxycarbamide in children receiving their first dose (HCnew) versus 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 versus time profiles were evaluated with a model independent approach in the HCnew and HCchronic 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 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.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/bcp.13426

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