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

不同年龄段羟基脲治疗镰状细胞性贫血的发育药理学

• 批准号: 10382052
• 负责人: Min Dong
• 金额: $ 19.6万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382052
• 关键词: Adolescence; Adult; Affect; Age; American; Applications Grants; Attention; Belief; Child; Childhood; Clinical; Clinical Pharmacology; Clinical Trials; Collaborations; Data; Data Set; Development; Disease; Dose; Drug Kinetics; Erythrocytes; Fetal Hemoglobin; Funding; Future; Gene therapy trial; Goals; Guidelines; Hematological Disease; Hematology; Hemoglobin; Hereditary Disease; Inherited; Life; Link; Maximum Tolerated Dose; Modeling; Molecular; Morbidity - disease rate; Myelosuppression; National Heart, Lung, and Blood Institute; National Institute of Child Health and Human Development; Nucleic Acid Regulatory Sequences; Patients; Pediatric Hematology; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacology; Physiological; Physiology; Population; Precision therapeutics; Regimen; Research; Safety; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; Solid; Symptoms; Time; Toxic effect; United States National Institutes of Health; Work; age related; appropriate dose; cohort; design; dose individualization; drug metabolism; effective therapy; experience; genome-wide; hydroxyurea; improved; individual variation; infancy; inhibitor; interpatient variability; methylome; mortality; multiple datasets; novel; novel therapeutics; pediatric patients; pharmacometrics; polymerization; precision medicine; predict clinical outcome; prevent; prospective; research study; response; transcriptome; treatment response

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.

项目摘要/摘要 镰状细胞贫血（SCA）是一种毁灭性的遗传性血液疾病，影响了100,000美国人和数百万 在世界范围内。没有治疗，SCA会导致巨大的发病率和早期死亡率。羟基脲 唯一具有可靠好处的药理学疗法可以改善SCA的临床过程。临床益处 羟基脲的主要是由于其增加胎儿血红蛋白（HBF）表达的能力，可防止 恶心的红细胞。当HBF的表达最高时，优化了羟基脲的好处， 这需要剂量升级至最大耐受剂量（MTD），其目标是轻度骨髓抑制。 但是，由于响应羟基脲处理的显着个体间异质性，并且 有效地升级为MTD所需的专业知识和时间，大多数接受了羟基脲治疗的患者 接受次优剂量，只有适度的治疗反应。通过NIH支持的治疗研究 （NCT02286154），我们已经开发并预先评估了一种个性化的药代动力学引导 SCA儿童的剂量模型，旨在优化羟基脲剂量和临床反应。这 剂量模型导致更高剂量和强大的HBF反应超出传统剂量 并与当前治愈基因疗法试验的目标匹配。这些结果表明，早期开始 使用个性化给药的第一年（虽然仍在表达HBF）中，羟基脲是更有效的 治疗模型比传统的给药策略。尽管有数十年的羟基脲研究和临床 经验，没有建立羟基脲和临床反应的明确关系，它 尚不清楚药物代谢或HBF表达和沉默的自然发育生理学如何 在整个年龄范围内影响羟基脲的影响。在此提案中，我们旨在进一步表征 与年龄相关的羟基脲的发育学药理学，以增强这种高效的使用 治疗。通过这些研究工作，我们旨在定量地表征发展 在整个年龄跨度的SCA儿童的羟基脲的药效学，以识别患者特异性 临床结局的生理预测指标，并确定最佳的起始年龄和给药方案 优化HBF响应和临床益处的目标。我们还旨在进一步探索强大的HBF归纳 对于从很小的时候开始开始羟基脲的儿童，以增强我们对此机制的理解 羟基脲诱导HBF以及该机制是否随着年龄的增长而变化。该建议是研究合作 在两个强大的共同理学之间，在小儿血液学和临床药理学方面具有专业知识，并且是立即的 对NICHD的重要呼吁的反应，以提高小儿精度疗法的安全性和功效。 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。这项研究将为个性化给药提供扎实的科学基础，并将 提高我们对如何以及何时为SCA患者使用羟基脲治疗的理解。