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Page 24 Pandey et al. J Transl Genet Genom 2021;5:22-36 I http://dx.doi.org/10.20517/jtgg.2020.45
[14]
targeting the prevention of symptoms . The treatment approaches for relief of symptoms include blood
transfusion and administration of antibiotics, opioids, and analgesics [3,14] . The treatments for symptoms
prevention include induction of fetal hemoglobin (HbF), targeting HbS polymerization, targeting
complications downstream of HbS polymerization, and curative intent therapies, which have recently been
reviewed elsewhere [15,16] . This manuscript focuses on the application of hydroxyurea and the rationale for
the development of an integrated population PK-PD model that may predict individual patient responses
to therapy and identify optimal dosing strategies.

Fetal hemoglobin (HbF; α γ ), the primary form of hemoglobin produced during fetal life, consists of two
2 2
α-globin subunits and two γ-globin subunits. After birth, expression of HbF is silenced as individuals
transition to adult hemoglobin (HbA; α β ) production. Since individuals with SCA produce HbS instead
2 2
[17]
of HbA, HbS polymerization leads to symptoms of SCA . Fetal hemoglobin inhibits HbS polymerization
[18]
by directly interfering with polymerization and by reducing the concentration of HbS production .
[18]
Hence, the elevation of HbF levels ameliorates the severity of SCA . The FDA approved drug for SCA
that induces HbF is hydroxyurea (HU). Prior to being identified as a therapy for SCA, HU was used as a
chemotherapeutic agent and in the treatment of HIV [19,20] . In individuals with SCA, HU reactivates HbF
production, thereby decreasing HbS polymerization, as discussed previously. The therapeutic effects of HU
include: increase in total hemoglobin by prolonging RBC life span; improvement in RBC hydration, thereby
decreasing HbS concentration and reducing polymerization; improvement in RBC rheology; reduction
of RBC-endothelial adhesion; and the potential increase in nitric oxide (NO), a potent vasodilator [17,21] .
Hydroxyurea inhibits ribonucleotide reductase, an enzyme essential for DNA synthesis, thereby causing
myelosuppression . Hydroxyurea is also associated with the normalization of usually elevated white blood
[22]
cells (WBC) by the primary effects of myelosuppression and the secondary effects of reducing ischemic
damage in the microvasculature [17,23,24] .

Long-term follow-ups of HU treatment showed increased survival of patients with no increased risk of
stroke, infection, or neoplasia [25,26] . Since HU therapy is associated with transient myelosuppression, routine
[14]
monitoring of blood counts is recommended during therapy . Routine laboratory monitoring during HU
therapy showed that individuals with SCA have an increased percentage of fetal hemoglobin (HbF%), total
hemoglobin level, and mean corpuscular volume (MCV) [27,28] . Although there is a large degree of individual
variability in response, increases in HbF% and MCV in HU-treated patients can be used as a surrogate for
medication adherence and clinical efficacy [29,30] .

Hydroxyurea treatment challenges
Heterogeneity of the disease and response
The type and degree of severity of SCD disease manifestations vary widely from patient to patient, likely
due to complex interactions between genetic and environmental disease modifiers. Additionally, patients
with SCD have a variable response to treatment with HU . Some patients respond well, and some are
[31]
poor responders to HU as determined by the percentage increase in HbF [21,27] . One therapeutic approach
for HU treatment is the personalization of a maximum tolerated dose (MTD) determined for individual
patients after careful monitoring of biomarkers and treatment response [29,31] . However, there is wide inter-
patient variability in the PK-PD of the drug inside the body [32-35] . This variability may arise due to each
patient having a different genetic, metabolic, and physiological makeup.

Timely and optimal prediction of dose
Clinicians define MTD using an adaptive dosing approach. In this empirical approach, the dosing starts
[14]
at 15-20 mg/kg, and the patient is monitored for excessive myelosuppression at the 4-6 weeks mark .
[14]
The dose is then increased in steps of 5 mg/kg every eight weeks up to a maximum of 35 mg/kg . The
therapeutic goal is to achieve an absolute neutrophil count of 1500-3000 cells/µL. The MTD determination