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

项目摘要/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。如果不进行治疗，SCA会导致巨大的发病率和早期死亡率。羟基脲是 唯一被证实对改善SCA临床病程有效的药物治疗。临床益处 羟基尿素的产生主要是由于它能够增加胎儿血红蛋白(HBF)的表达，从而防止 红血球呈镰状。当HbF的表达最高时，羟基脲的效益最佳， 这需要将剂量升级到最大耐受剂量(MTD)，目标是轻度骨髓抑制。 然而，由于对羟基尿素治疗的反应存在显著的个体间异质性，并且 有效地将剂量增加到MTD所需的专业知识和时间，大多数患者使用羟基脲治疗 接受次优剂量，并且只有轻微的治疗反应。通过美国国立卫生研究院支持的治疗研究 (NCT02286154)，我们已经开发并前瞻性地评估了一种个性化的、以药物动力学为导向的 SCA患儿给药模型，旨在优化羟基尿素用量和临床疗效。这 剂量模式导致了比传统剂量更高的剂量和强大的HBF反应 与目前治疗性基因治疗试验的目标不相上下。这些结果表明，早期启动 在生命的第一年(尽管HbF仍在表达)使用个体化剂量是更有效的 治疗模式优于传统的给药策略。尽管几十年来羟基脲的研究和临床 根据经验，羟基尿素暴露与临床反应之间没有明确的关系，而且它 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 跨年龄跨度影响羟基尿素的效果。在这项提案中，我们的目标是进一步描述 羟基脲的年龄相关发育药理学，以努力提高这种高效的用途 心理治疗。通过这些研究努力，我们的目标是定量地表征发展的 羟基脲对跨年龄段SCA儿童的药效学研究 临床结果的生理学预测因素，并确定最佳开始年龄和给药方案 优化HBF反应和临床效益的目标。我们还打算进一步探索健壮的HBF诱导 对于儿童在很小的年龄就开始使用羟基尿素，以增强我们对其作用机制的了解 羟基脲可诱发HBF，其机制是否随年龄变化而变化。这项提议是一项研究合作 在两个在儿科血液学和临床药理学方面具有专业知识的强大合作PIs之间，是一个直接的 响应NICHD的一项重要呼吁，提高儿科精确治疗的安全性和有效性。 我们将分析来自世界各地临床试验的多个数据集，其中包括1000多名患有SCA的儿童 用羟基脲处理。这项研究将为个体化给药提供坚实的科学依据，并将 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.