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Clinical Trial
. 2016 Mar;56(3):298-306.
doi: 10.1002/jcph.598. Epub 2015 Oct 15.

Pharmacokinetics and bioequivalence of a liquid formulation of hydroxyurea in children with sickle cell anemia

Jeremie H Estepp  1 , Chiara Melloni  2 , Courtney D Thornburg  3 , Paweł Wiczling  4 , Zora Rogers  5 , Jennifer A Rothman  6 , Nancy S Green  7 , Robert Liem  8 , Amanda M Brandow  9 , Shelley E Crary  10 , Thomas H Howard  11 , Maurine H Morris  12 , Andrew Lewandowski  13 , Uttam Garg  14 , William J Jusko  15 , Kathleen A Neville  16 ; Best Pharmaceuticals for Children Act-Pediatric Trials Network Administrative Core Committee
Collaborators, Affiliations
Clinical Trial

Pharmacokinetics and bioequivalence of a liquid formulation of hydroxyurea in children with sickle cell anemia

Jeremie H Estepp et al. J Clin Pharmacol. 2016 Mar.

Abstract

Hydroxyurea (HU) is a crucial therapy for children with sickle cell anemia, but its off-label use is a barrier to widespread acceptance. We found HU exposure is not significantly altered by liquid vs capsule formulation, and weight-based dosing schemes provide consistent exposure. HU is recommended for all children starting as young as 9 months of age with sickle cell anemia (SCA; HbSS and HbSβspan(0) thalassemia); however; a paucity of pediatric data exists regarding the pharmacokinetics (PK) or the exposure-response relationship of HU. This trial aimed to characterize the PK of HU in children and to evaluate and compare the bioavailability of a liquid vs capsule formulation. This multicenter; prospective; open-label trial enrolled 39 children with SCA who provided 682 plasma samples for PK analysis following administration of HU. Noncompartmental and population PK models are described. We report that liquid and capsule formulations of HU are bioequivalent; weight-based dosing schemes provide consistent drug exposure; and age-based dosing schemes are unnecessary. These data support the use of liquid HU in children unable to swallow capsules and in those whose weight precludes the use of fixed capsule formulations. Taken with existing safety and efficacy literature; these findings should encourage the use of HU across the spectrum of age and weight in children with SCA; and they should facilitate the expanded use of HU as recommended in the National Heart; Lung; and Blood Institute guidelines for individuals with SCA.

Keywords: bioequivalent; hydroxyurea. children; sickle cell anemia.

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Conflict of interest statement

Conflict-of-Interest Disclosures

Jeremie H. Estepp receives funding support from Daiichi Sankyo and Eli Lilly and Co. Courtney D. Thornburg has research funding from MAST Pharmaceuticals for sickle-cell-related research; she also received NIH funding for the BABY HUG follow-up studies. Zora Rogers has received honoraria and consultation work from Apopharma, Baxter, Roche, and GSK as well as from the Texas Department of State Health Services. Shelley E. Crary has served on the advisory board for hemophilia for Grifols. The other authors have no potential conflicts to report.

Figures

Figure 1
Figure 1
Representative hydroxyurea concentration (μg/mL) per time (hour) profiles in 4 selected children who were given both liquid (–○–) and capsule (–●–) formulations.
Figure 2
Figure 2
Relationship of body-weight-normalized apparent clearances (CL/F/BW and CL/F/BW^0.75) vs age for all children. Closed symbols (●) denote males, and open symbols (○) denote females.
See this image and copyright information in PMC

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