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Pandey et al. J Transl Genet Genom 2021;5:22-36 Journal of Translational
DOI: 10.20517/jtgg.2020.45 Genetics and Genomics

Review Open Access

Hydroxyurea treatment of sickle cell disease:
towards a personalized model-based approach

Akancha Pandey , Jeremie H. Estepp , Doraiswami Ramkrishna 1
2
1
1 Davidson School of Chemical Engineering, Purdue University, West Lafayette, IN 47907, USA.
2 Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
Correspondence to: Dr. Doraiswami Ramkrishna, Davidson School of Chemical Engineering, Purdue University, Forney Hall of
Chemical Engineering, 480 Stadium Mall Drive, West Lafayette, IN 47907-2100, USA. E-mail: ramkrish@ecn.purdue.edu
How to cite this article: Pandey A, Estepp JH, Ramkrishna D. Hydroxyurea treatment of sickle cell disease: towards a personalized
model-based approach. J Transl Genet Genom 2021;5:22-36. http://dx.doi.org/10.20517/jtgg.2020.45
Received: 9 Sep 2020 First Decision: 9 Oct 2020 Revised: 6 Nov 2020 Accepted: 19 Nov 2020 Available online: 26 Jan 2021

Academic Editor: Ramón Cacabelos Copy Editor: Miao Zhang Production Editor: Jing Yu

Abstract
Hydroxyurea is a commonly used drug for the treatment of sickle cell disease. Several studies have demonstrated
the efficacy of hydroxyurea in ameliorating disease pathophysiology. However, a lack of consensus on optimal
dosing and the need for ongoing toxicity monitoring for myelosuppression limits its utilization. Pharmacokinetic
(PK) and pharmacodynamic (PD) studies describe drug-body interactions, and hydroxyurea PK-PD studies have
reported wide inter-patient variability. This variability can be explained by a mathematical model taking into
consideration different sources of variation such as genetics, epigenetics, phenotypes, and demographics. A PK-PD
model provides us with a tool to capture these variant responses of patients to a given drug. The development of an
integrated population PK-PD model that can predict individual patient responses and identify optimal dosing would
maximize efficacy, limit toxicity, and increase utilization. In this review, we discuss various treatment challenges
associated with hydroxyurea. We summarize existing population PK-PD models of hydroxyurea, the gap in the
existing models, and the gap in the mechanistic understanding. Lastly, we address how mathematical modeling can
be applied to improve our understanding of hydroxyurea’s mechanism of action and to tackle the challenge of inter-
patient variability, dose optimization, and non-adherence.

Keywords: Sickle cell disease, hydroxyurea, fetal hemoglobin, pharmacokinetics, pharmacodynamics

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0
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