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 Liem; Amanda M. Brandow; Shelley E. Crary; Thomas H. Howard; Maurine H. Morris; Andrew Lewandowski; Uttam Garg; William J. Jusko; Kathleen A. Neville

doi:10.1002/jcph.598

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 Liem, Amanda M. Brandow, Shelley E. Crary, Thomas H. Howard, Maurine H. Morris, Andrew Lewandowski, Uttam Garg, William J. Jusko, Kathleen A. Neville

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17 Scopus citations

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 language	English (US)
Pages (from-to)	298-306
Number of pages	9
Journal	Journal of clinical pharmacology
Volume	56
Issue number	3
DOIs	https://doi.org/10.1002/jcph.598
State	Published - Mar 1 2016

Keywords

bioequivalent
hydroxyurea. children
sickle cell anemia

ASJC Scopus subject areas

Pharmacology
Pharmacology (medical)

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10.1002/jcph.598

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Estepp, J. H., Melloni, C., Thornburg, C. D., Wiczling, P., Rogers, Z., Rothman, J. A., Green, N. S., Liem, R., Brandow, A. M., Crary, S. E., Howard, T. H., Morris, M. H., Lewandowski, A., Garg, U., Jusko, W. J., & 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, JH, Melloni, C, Thornburg, CD, Wiczling, P, Rogers, Z, Rothman, JA, Green, NS, Liem, R, 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

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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 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.",

keywords = "bioequivalent, hydroxyurea. children, sickle cell anemia",

author = "Estepp, {Jeremie H.} and Chiara Melloni and Thornburg, {Courtney D.} and Pawe{\l} Wiczling and Zora Rogers and Rothman, {Jennifer A.} and Green, {Nancy S.} and Robert Liem and Brandow, {Amanda M.} and Crary, {Shelley E.} and Howard, {Thomas H.} and Morris, {Maurine H.} and Andrew Lewandowski and Uttam Garg and Jusko, {William J.} and Neville, {Kathleen A.}",

note = "Publisher Copyright: {\textcopyright} 2015, The American College of Clinical Pharmacology.",

year = "2016",

month = mar,

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doi = "10.1002/jcph.598",

language = "English (US)",

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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

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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JO - Journal of clinical pharmacology

JF - Journal of clinical pharmacology

IS - 3

ER -

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

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