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

项目概要/摘要 镰状细胞性贫血（SCA）是一种毁灭性的遗传性血液疾病，影响10万美国人和数百万人。 在世界各地。如果不治疗，SCA会导致巨大的发病率和早期死亡率。羟基脲 是唯一一种经证实有益于改善SCA临床病程的药物治疗。的临床受益 主要是由于它能够增加胎儿血红蛋白（HbF）的表达，从而防止 红细胞的镰状化。当HbF的表达最高时， 其需要剂量递增至最大耐受剂量（MTD），目标是轻度骨髓抑制。 然而，由于对羟基脲治疗反应的显著个体间异质性， 有效递增剂量至MTD所需的专业知识和时间，大多数接受羟基脲治疗的患者 接受次优剂量并且只有适度的治疗反应。通过NIH支持的TREAT研究， （NCT 02286154），我们开发并前瞻性评价了一种个体化的药代动力学指导的 SCA儿童的剂量模型，旨在优化羟基脲剂量和临床反应。这 给药模型导致了更高的剂量和稳健的HbF反应，超出了传统给药的效果 并与当前治愈性基因治疗试验的目标相媲美。这些结果表明， 在生命的第一年（HbF仍表达时）使用个体化给药是一种更有效的方法。 治疗模式比传统的给药策略。尽管几十年来对羟基脲的研究和临床 根据经验，尚未确定羟基脲暴露与临床反应的明确关系， 目前尚不清楚药物代谢或HbF表达和沉默的自然发育生理学 影响了羟基脲的作用。在本提案中，我们旨在进一步描述 年龄相关的发展药理学的羟基脲，努力提高使用这种高效 疗法通过这些研究工作，我们的目标是定量表征发展 在不同年龄段的SCA儿童中使用羟基脲的药效学，以确定患者特异性 临床结果的生理学预测因素，并确定最佳起始年龄和给药方案， 优化HbF反应和临床益处的目标。我们还旨在进一步探索HbF诱导的稳健性。 儿童在很小的时候就开始使用羟基脲，以加强我们对 羟基脲诱导HbF以及这种机制是否随年龄而变化。这是一个研究合作项目 两个具有儿科血液学和临床药理学专业知识的强有力的共同PI之间， 这是对NICHD提高儿科精确治疗安全性和有效性的重要呼吁的回应。 我们将分析来自世界各地临床试验的多个数据集，包括1000多名SCA儿童 用羟基脲处理。这项研究将为个体化给药提供坚实的科学基础， 提高我们对如何以及何时使用羟基脲治疗儿童SCA患者的理解。

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.