title: Pharmacokinetics and bioequivalence of a liquid formulation of hydroxyurea in children with sickle cell anemia.
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.
authors.affiliation: Departments of Hematology and Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Jeremie H
authors.initials: JH
authors.lastname: Estepp
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: Chiara
authors.initials: C
authors.lastname: Melloni
authors.affiliation: Department of Pediatrics, University of California-San Diego, La Jolla, CA, USA.
authors.forename: Courtney D
authors.initials: CD
authors.lastname: Thornburg
authors.affiliation: Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Wiczling
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Zora
authors.initials: Z
authors.lastname: Rogers
authors.affiliation: Division of Pediatric Hematology/Oncology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Rothman
authors.affiliation: Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Columbia University Medical Center, New York, NY, USA.
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Green
authors.affiliation: Division of Hematology, Oncology, and Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Liem
authors.affiliation: Section of Pediatric Hematology/Oncology, Medical College of Wisconsin, and Children's Research Institute of the Children's Hospital of Wisconsin, Milwaukee, WI, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Brandow
authors.affiliation: Division of Pediatric Hematology-Oncology, University of Arkansas for Medical Sciences/Arkansas Children's Hospital, Little Rock, AR, USA.
authors.forename: Shelley E
authors.initials: SE
authors.lastname: Crary
authors.affiliation: Division of Pediatric Hematology and Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Howard
authors.affiliation: Duke Clinical Research Institute, Durham, NC, USA.
authors.forename: Maurine H
authors.initials: MH
authors.lastname: Morris
authors.affiliation: The Emmes Corporation, Rockville, MD, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lewandowski
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Mercy Hospitals and Clinics, Kansas City, MO, USA.
authors.forename: Uttam
authors.initials: U
authors.lastname: Garg
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Jusko
authors.affiliation: Section of Pharmacology and Toxicology, University of Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, AR, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Neville
mesh_terms: D000293:Adolescent; D000755:Anemia, Sickle Cell / Q000097:blood*; D000986:Antisickling Agents / Q000097:blood / Q000493:pharmacokinetics; D002214:Capsules; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D008297:Male; D011446:Prospective Studies; D012996:Solutions; D013810:Therapeutic Equivalency
chemical_list: D000986:Antisickling Agents; D002214:Capsules; D012996:Solutions; D006918:Hydroxyurea
keywords: bioequivalent; hydroxyurea. children; sickle cell anemia