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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 33

Figure 2. A modeling framework for optimal dose calculation. D(t): HU dose; y p :HU plasma concentration; y m : metabolite concentration;
HbF: fetal hemoglobin concentration; MCV: mean cell volume of red blood cell; ANC: absolute neutrophil count; ARC: absolute
reticulocytes count

Quantify non-adherence
As described in the section on Hydroxyurea Treatment Challenges, there is a need to quantify non-
adherence using a mathematical model that can predict patient response and differentiate non-adherent
patients from non-responders.

In PK-PD studies of HU, it is seen that there is a time lag in the drug expression in the plasma and the drug
response. The timescale for change in HU in the plasma is in hours, as observed from PK studies [32,34,35] .
However, the change in the response variables is seen after weeks of hydroxyurea exposure [21,27] . The reason
behind the time lag in the PK-PD profiles of HU is not fully understood. The underlying mechanism of
how HU stimulates HbF synthesis, how it increases the MCV of RBC, and how it causes myelosuppression
is not fully understood. To address the above, the various factors influencing the PK-PD trajectory of HU
need to be understood. Further work needs to be done to identify the HU transporters, metabolites, and
enzymes involved. The signaling pathway involved in HbF stimulation needs to be identified through new
experiments. The mechanism of how HU affects cells in the different stages of hematopoiesis will aid in
elucidating the drug-dependent myelosuppression.

The current state of mathematical model development in HU treatment of SCD patients aims towards
building a population PK-PD model to predict individual patient PK and the relation between exposure
and efficacy [Tables 1 and 2]. The recent developments in population PK models have shown promising
results in predicting varying PK profiles of patients [33-35,54] . However, there has been little effort to link the
[33]
PK and PD models of HU. Besides, the PD model only considered efficacy and did not include toxicity .
A detailed PD model based on HU efficacy and toxicity is needed, which can predict the dynamics of
individual patient response and can be tweaked to generate the desired response. There is also a need
to integrate the systems biology approach with PK-PD modeling to develop mechanistic models of the
drug-disease dynamics. Mathematical models can give new insight and improve the understanding of the
mechanism of SCD progression and modification in the presence of HU, thereby advancing the treatment
and improving the quality of life of SCD patients.

DECLARATIONS
Acknowledgments
Pandey A would like to thank Lina Aboulmouna, Kaushal Jain, and Parul Verma for reviewing the
manuscript.

Authors’ contributions
Reviewed literature and wrote the manuscript: Pandey A
Provided critical review and editing of the manuscript: Estepp JH
Provided critical review of the manuscript: Ramkrishna D