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Eur J Pharm Sci. 2019 Oct 1;138:105013. doi: 10.1016/j.ejps.2019.105013. Epub 2019 Jul 21.

Target-mediated disposition population pharmacokinetics model of erythropoietin in premature neonates following multiple intravenous and subcutaneous dosing regimens.

Author information

1
Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA.
2
Department of Pediatrics Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
3
Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, USA.
4
School of Pharmacy, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
5
Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA; MedImmune, LLC., San Francisco, CA, USA.
6
Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA. Electronic address: guohua-an@uiowa.edu.

Abstract

Routine erythropoietin (Epo) therapy for neonatal anemia is presently controversial due to its modest response. We speculate that an important contributor to this modest response is that previous clinical study designs were not driven by rigorous mechanistic and kinetic insights into the complex pharmacokinetics (PK) and pharmacodynamics (PD) of Epo in this population. To address this therapeutic opportunity, we conducted a prospective clinical study to investigate the PK of Epo in very-low-birth-weight (VLBW) premature neonates using a unique Epo dosing algorithm that accounts for complex neonatal erythropoietic physiology. Twenty-seven subjects received up to 10 intravenous or subcutaneous exogenous doses of Epo (600 or 1200 U/kg) during the first 4 weeks of life. Subjects were administered two doses of Epo 1200 U/kg on days 2 and 16, and eight doses of Epo 600 U/kg on days 4, 5, 6, 7, 9, 14, 15, and 28 following birth. We have developed for the first time a mechanistic, target-mediated disposition model that provides novel insights into the mechanisms driving Epo PK in VLBW neonates. Epo association rate, kon, was estimated to be 0.00610 pM-1h-1, and the dissociation rate koff was 0.112 h-1. Internalization of the Epo-target complex (kint) and the total receptor concentration (Rmax) were estimated to be 0.118 h-1 and 133 pM, respectively. Following s.c. administration, the absorption rate (ka) of Epo was 0.0738h-1 and bioavailability was 78.0%. Our mechanism-based population pharmacokinetic analysis provided quantitative insight into Epo kinetics in VLBW neonates; the information gained will assist in deriving dosing strategies for neonatal anemia and for neuroprotection efficacy studies.

KEYWORDS:

Erythropoietin; Population pharmacokinetics; Premature neonates; Target-mediated drug disposition

PMID:
31340188
PMCID:
PMC6733583
[Available on 2020-10-01]
DOI:
10.1016/j.ejps.2019.105013
[Indexed for MEDLINE]

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