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

Jeremie H. Estepp, Chiara Melloni, Courtney D. Thornburg, Paweł Wiczling, Zora Rogers, Jennifer A. Rothman, Nancy S. Green, Robert I Liem, Amanda M. Brandow, Shelley E. Crary, Thomas H. Howard, Maurine H. Morris, Andrew Lewandowski, Uttam Garg, William J. Jusko, Kathleen A. Neville*

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 HbSβspan0thalassemia); 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.

Original languageEnglish (US)
Pages (from-to)298-306
Number of pages9
JournalJournal of Clinical Pharmacology
Volume56
Issue number3
DOIs
StatePublished - Mar 1 2016

Fingerprint

Therapeutic Equivalency
Hydroxyurea
Sickle Cell Anemia
Pharmacokinetics
Capsules
Weights and Measures
Off-Label Use
Deglutition
Biological Availability
Guidelines
Pediatrics
Safety
Lung

Keywords

  • bioequivalent
  • hydroxyurea. children
  • sickle cell anemia

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Estepp, J. H., Melloni, C., Thornburg, C. D., Wiczling, P., Rogers, Z., Rothman, J. A., ... Neville, K. A. (2016). Pharmacokinetics and bioequivalence of a liquid formulation of hydroxyurea in children with sickle cell anemia. Journal of Clinical Pharmacology, 56(3), 298-306. https://doi.org/10.1002/jcph.598
Estepp, Jeremie H. ; Melloni, Chiara ; Thornburg, Courtney D. ; Wiczling, Paweł ; Rogers, Zora ; Rothman, Jennifer A. ; Green, Nancy S. ; Liem, Robert I ; Brandow, Amanda M. ; Crary, Shelley E. ; Howard, Thomas H. ; Morris, Maurine H. ; Lewandowski, Andrew ; Garg, Uttam ; Jusko, William J. ; Neville, Kathleen A. / Pharmacokinetics and bioequivalence of a liquid formulation of hydroxyurea in children with sickle cell anemia. In: Journal of Clinical Pharmacology. 2016 ; Vol. 56, No. 3. pp. 298-306.
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Estepp, JH, Melloni, C, Thornburg, CD, Wiczling, P, Rogers, Z, Rothman, JA, Green, NS, Liem, RI, Brandow, AM, Crary, SE, Howard, TH, Morris, MH, Lewandowski, A, Garg, U, Jusko, WJ & Neville, KA 2016, 'Pharmacokinetics and bioequivalence of a liquid formulation of hydroxyurea in children with sickle cell anemia', Journal of Clinical Pharmacology, vol. 56, no. 3, pp. 298-306. https://doi.org/10.1002/jcph.598

Pharmacokinetics and bioequivalence of a liquid formulation of hydroxyurea in children with sickle cell anemia. / Estepp, Jeremie H.; Melloni, Chiara; Thornburg, Courtney D.; Wiczling, Paweł; Rogers, Zora; Rothman, Jennifer A.; Green, Nancy S.; Liem, Robert I; Brandow, Amanda M.; Crary, Shelley E.; Howard, Thomas H.; Morris, Maurine H.; Lewandowski, Andrew; Garg, Uttam; Jusko, William J.; Neville, Kathleen A.

In: Journal of Clinical Pharmacology, Vol. 56, No. 3, 01.03.2016, p. 298-306.

Research output: Contribution to journalArticle

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T1 - Pharmacokinetics and bioequivalence of a liquid formulation of hydroxyurea in children with sickle cell anemia

AU - Estepp, Jeremie H.

AU - Melloni, Chiara

AU - Thornburg, Courtney D.

AU - Wiczling, Paweł

AU - Rogers, Zora

AU - Rothman, Jennifer A.

AU - Green, Nancy S.

AU - Liem, Robert I

AU - Brandow, Amanda M.

AU - Crary, Shelley E.

AU - Howard, Thomas H.

AU - Morris, Maurine H.

AU - Lewandowski, Andrew

AU - Garg, Uttam

AU - Jusko, William J.

AU - Neville, Kathleen A.

PY - 2016/3/1

Y1 - 2016/3/1

N2 - 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 HbSβspan0thalassemia); 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.

AB - 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 HbSβspan0thalassemia); 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.

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