# Developmental Pharmacology of Hydroxyurea Across the Age Span for the Treatment of Sickle Cell Anemia

> **NIH NIH R21** · RHODE ISLAND HOSPITAL · 2022 · $195,993

## Abstract

PROJECT SUMMARY/ABSTRACT
Sickle cell anemia (SCA) is a devastating inherited blood disorder, affecting 100,000 Americans and millions
across the world. Without treatment, SCA results in tremendous morbidity and early mortality. Hydroxyurea is
the only pharmacologic therapy with proven benefits to ameliorate the clinical course of SCA. The clinical benefits
of hydroxyurea are due mostly to its ability to increase the expression of fetal hemoglobin (HbF), which prevents
sickling of red blood cells. The benefits of hydroxyurea are optimized when the expression of HbF is the highest,
which requires dose escalation to maximum tolerated dose (MTD) with a goal of mild myelosuppression.
However, due to the significant inter-individual heterogeneity in response to hydroxyurea treatment, and the
expertise and time required to escalate the dose effectively to MTD, most patients treated with hydroxyurea
receive suboptimal doses and have only modest treatment responses. Through the NIH-supported TREAT study
(NCT02286154), we have developed and prospectively evaluated an individualized, pharmacokinetics-guided
dosing model for children with SCA, designed to optimize the hydroxyurea dose and clinical response. This
dosing model has resulted in higher doses and robust HbF responses beyond what is seen with traditional dosing
and rivaling the goal of current curative gene therapy trials. These results suggest that early initiation of
hydroxyurea in the first year of life (while HbF is still expressed) using individualized dosing is a more effective
treatment model than traditional dosing strategies. Despite decades of hydroxyurea research and clinical
experience, no clear relationship of hydroxyurea exposure and clinical response has been established, and it
remains unclear how natural developmental physiology of drug metabolism or HbF expression and silencing
across the age span influence the effects of hydroxyurea. In this proposal, we aim to further characterize the
age-related developmental pharmacology of hydroxyurea in an effort to enhance the usage of this highly effective
therapy. Through these research efforts, we aim to quantitatively characterize the developmental
pharmacodynamics of hydroxyurea for children with SCA across the age span, to identify patient-specific
physiological predictors of clinical outcome, and to determine the optimal starting age and dosing regimen with
a goal of optimizing HbF response and clinical benefits. We also aim to further explore the robust HbF induction
for children starting hydroxyurea at a very early age to enhance our understanding of the mechanism by which
hydroxyurea induces HbF and whether this mechanism varies with age. This proposal is a research collaboration
between two strong co-PIs with expertise in pediatric hematology and clinical pharmacology and is an immediate
response to an important call from the NICHD to improve the safety and efficacy of pediatric precision therapies.
We will analyze multiple datas...

## Key facts

- **NIH application ID:** 10382052
- **Project number:** 1R21HD107675-01
- **Recipient organization:** RHODE ISLAND HOSPITAL
- **Principal Investigator:** Min Dong
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $195,993
- **Award type:** 1
- **Project period:** 2022-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10382052

## Citation

> US National Institutes of Health, RePORTER application 10382052, Developmental Pharmacology of Hydroxyurea Across the Age Span for the Treatment of Sickle Cell Anemia (1R21HD107675-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10382052. Licensed CC0.

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