Page 74 - Read Online

Pandey et al. J Transl Genet Genom 2021;5:22-36 I http://dx.doi.org/10.20517/jtgg.2020.45 Page 25

usually takes 9-12 months of treatment. If the optimal dose can be determined earlier using mathematical
modeling, the time to MTD can be reduced, and, as a result, maximum benefits from HU can be extracted.

Non-adherence to treatments
Non-adherence presents a significant challenge for clinicians. The effect of HU is maximized with
adherence to daily administration, and the benefits wane with non-adherence. Clinically, it is challenging
to differentiate treatment inefficacy from non-adherence, and doctors may confuse the non-adherence to
[36]
the patient being treatment refractory. Thornburg et al. evaluated adherence in children with SCA treated
on HU therapy and found that good adherence led to an increase in HbF% inferred from a moderate
association between HbF% and Morisky score and number of refills. Brandow and Panepinto classified
[37]
barriers to the use of hydroxyurea as provider-related, patient-related, and system-related ones . They
identified several barriers to adherence to HU therapy: the delayed benefits of HU, fear of drug side effects,
expected frequent treatment monitoring, forgetfulness, and poor access to healthcare [36,37] .

Need for effective biomarkers
[27]
The biomarkers currently in use are HbF and MCV of RBC, both of which increase with HU treatment .
However, they take some time to reach a steady-state, and there is a large degree of intra-patient variability
in response. Therefore, there is a need for a better biomarker to detect treatment efficacy earlier.

Incomplete understanding of the drug mechanism
The mechanism of HU-induced HbF stimulation is not known, and the transporters, enzymes,
metabolites, and signaling molecules involved in HU PK-PD are not known. The potential role of organic
anion transporting polypeptides (OATP) as HU transporters was investigated [38,39] . Studies showed that
metabolites such as urea, nitric oxide were produced, and enzymes such as monooxygenase and catalase
were involved in the metabolism of HU [40-42] . Studies have indicated the nitric oxide-cyclic guanosine
monophosphate signaling pathway or p38 mitogen-activated protein kinase pathway to be activated when
HU is administered in vitro [43-45] . Understanding the drug mechanism will help in advancing the HU
treatment further.

Myelosuppression
[2]
As mentioned above, HU inhibits enzyme ribonucleotide reductase, which causes bone marrow toxicity .
A dose-dependent decrease in neutrophils and reticulocytes follows HU administration. HU-induced
[21]
increase in HbF% is correlated to change in MCV, neutrophils, and reticulocytes count . Neutrophil
count < 2000/µL, reticulocyte count < 80,000/µL, platelet count < 80,000/µL, and hemoglobin concentration
[21]
< 4.5 g/dL are considered excessive myelosuppression . When excessive myelosuppression events are
[46]
repeated, the treatment is withheld for 1-2 weeks until cell counts normalize . Following this, HU is
resumed at a lower dose than the toxic dose.

All these challenges reflect the need for a mathematical model to address and further explore mechanisms
of HbF activation. We need a treatment regimen guided by patients’ history and patient-specific variables
to decide an adequate dose for every patient. The standard clinical practice of determining the MTD is time
and effort consuming and requires constant monitoring of the patient. A mathematical model would be
clinically useful in predicting the inter-patient variability by considering individual patients’ biochemical
and genetic composition and demographic variables. A mathematical model will also help the timely and
optimal dosage prediction by maximizing efficacy and minimizing toxicity. Through the model, we can
look for alternative biomarkers that do not take a longer time to reach a steady-state.

PHARMACOKINETICS AND PHARMACODYNAMICS OF HYDROXYUREA
Hydroxyurea is used for the treatment of cancer, HIV, and sickle cell disease. Pharmacokinetics mainly
consists of four processes: absorption, distribution, metabolism, and excretion (ADME). Hydroxyurea