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Pandey et al. J Transl Genet Genom 2021;5:22-36 I http://dx.doi.org/10.20517/jtgg.2020.45 Page 23

INTRODUCTION
Sickle cell disease (SCD) is a hereditary disease affecting up to an estimated 100,000 people in the United
[1]
States and millions worldwide . SCD is caused by a point mutation in the β-globin gene that results
in a single nucleotide substitution, changing glutamic acid (GAG) to valine (GTG) in the sixth codon,
[2]
and subsequently produces abnormal sickle hemoglobin (HbS) . Sickle hemoglobin polymerizes upon
[3]
deoxygenation in the peripheral microvasculature and forms an elongated, rod-like structure . The
polymerized structure stretches the red blood cell (RBC) and deforms the membrane producing rigid and
[4]
sickle-shaped RBCs . The sickled RBC adheres to endothelial cells and is responsible for the vaso-occlusive
crisis . The primary clinical effects associated with vaso-occlusive complications are painful episodes,
[5]
[3]
acute chest syndrome, and stroke . Sickle cell anemia (SCA) describes the homozygous condition when
[4,5]
both the genes for β-globin (β ) are mutated, and SCA is represented by the HbSS genotype . Besides
s
0
the homozygous HbSS genotype, other genotypes of SCD include heterozygous sickle-cell/β thalassemia
+
0
(HbS/β ), sickle-cell/β thalassemia (HbS/β ), sickle-cell/hemoglobin C disease (HbSC), and other rare
+
[7]
[5,6]
genotypes . A wide degree of phenotypic variability is observed in addition to genetic variability .
Mathematical models have been developed for several diseases, such as hematological malignancies,
solid tumors, diabetes, and human immunodeficiency viruses (HIV), to address the ongoing treatment
challenges ranging from improving the existing drug dosing regimen to the effective management of
the disease adverse events. A model-guided dosing strategy can be applied to predict drug-dependent
efficacy and toxicity at multiple stages of treatment. For example, the pharmacokinetic-pharmacodynamic
(PK-PD) modeling of the drugs cisplatin and etoposide for small-cell lung cancer identified three new
dosing regimens with a better reduction in tumor size compared to standard protocol while satisfying
toxicity constraints for neutrophil and platelet counts . Similarly, Houy and Grand determined optimal
[8]
[9]
chemotherapy regimens for temozolomide using the PK-PD modeling . The model showed that the
[9]
toxicity of metronomic chemotherapy could be reduced while achieving the same level of efficacy .
Another successful use of a model-based approach in treatment efficacy was to personalize the
6-mercaptopurine treatment of acute lymphoblastic leukemia [10,11] . The model factored in the patient-
specific variations in enzyme, thiopurine methyltransferase (TPMT), activity to obtain optimal dose. The
study showed that a lower dose is needed for a patient with low TPMT enzyme activity than the standard
[10]
dose . Mathematical model-based approaches have been developed for diabetes, where both clinical and
[12]
non-clinical models are available . The clinical models include models developed for describing diagnosis,
control, progression, and complications. The non-clinical models aid in unraveling the mechanism of
[12]
insulin-glucose dynamics on multi-scale levels . Mathematical models have also been used to study HIV
[13]
dynamics, to understand disease progression, and to improve treatment . Similar mathematical modeling
approaches can be leveraged for describing SCD progression and the influence of hydroxyurea on disease
modification.

The need for a model-based approach arises from the treatment challenges faced by clinicians in
managing SCD. In this review, we discuss the challenges associated with hydroxyurea treatment. The
pharmacokinetics and pharmacodynamics of hydroxyurea are discussed with a focus on population PK-PD
modeling. This review elaborates on building a personalized treatment strategy by formulating patient PK-PD
models and integrating them. The modeling strategy can be applied to predict an individual patient’s
treatment response trajectory with time and determine personalized dosage.

TREATMENT APPROACHES
The treatment approach for SCD varies from patient to patient depending on the stage of the disease
and clinical severity. The treatment includes two types of strategies: targeting the relief of symptoms and