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

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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 datasets from clinical trials across the world, including over 1000 children with SCA treated with hydroxyurea. This research will provide a solid scientific basis for individualized dosing and will improve our understanding of how and when to use hydroxyurea therapy for pediatric patients with SCA.