Hydroxyurea Pharmacokinetics and Pharmacogenomics

描述（由申请人提供）：羟基脲用于儿童和成人镰状细胞性贫血（SCA）的使用正在增加，但存在实质性的个体间差异，限制了其作为常规有效治疗剂的效用。例如，药物剂量变化很大，个体患者的最大耐受剂量（MTD）在10至35 mg/kg/天之间变化。一些患者在相对低剂量下出现血液学毒性，HbF反应温和，而另一些患者耐受更高剂量，HbF反应更强。羟基脲治疗的血液学反应各不相同，MTD时HbF水平从5%到30%不等，即使对于粘附患者也是如此。治疗减少溶血（降低LDH）也是可变的，虽然没有很好地描述。我们的初步数据表明，与药物吸收和处置相关的羟基脲药代动力学存在显著的个体间差异，这可能影响SCA患者羟基脲治疗的实验室反应和毒性特征。在特异性目标1中，我们将描述羟基脲治疗SCA患儿的药代动力学表型。我们假设羟基脲治疗在SCA中有两种不同的药代动力学特征，基于达到峰值吸收的时间。为了验证这一假设，我们将前瞻性地测量首次给药羟基脲的药代动力学，以记录个体间的差异，并确定不同的表型。在专项目标2中，我们将研究羟基脲药代动力学表型和药物效应之间的关系。我们假设药代动力学差异会影响羟基脲的反应，因此我们将收集经羟基脲治疗的SCA患者的前瞻性药代动力学数据，这些患者的MTD值是可变的% HbF、血清LDH或MTD值。羟基脲在MTD处的不同反应表型已被确定，包括高HbF与低HbF、低MTD和高LDH，尽管HbF诱导良好。在特异性目标3中，我们将研究羟基脲治疗中表型变异的遗传基础。我们假设特定的遗传差异影响羟基脲治疗观察到的表型。为了验证这一假设，我们将研究与羟基脲的吸收、运输和代谢有关的候选基因，所有这些基因都可能影响药物的药代动力学。参与羟基脲治疗的细胞效应的基因位点也将被研究。公共卫生相关性：本研究计划的总体目标是研究羟基脲治疗SCA患者的药理学变异性，特别是更好地了解剂量、毒性和实验室反应的个体间差异。长期目标是利用羟基脲治疗的药代动力学、药效学和药物基因组学信息来帮助预测个体患者的药物效应，并最终改善SCA患者的医疗护理。

DESCRIPTION (provided by applicant): The use of hydroxyurea for children and adults with sickle cell anemia (SCA) is increasing, but substantial inter-individual differences exist that limit its utility as a routine and effective therapeutic agent. For example, the drug dosing is highly variable, with the maximum tolerated dose (MTD) for individual patients varying between 10 and 35 mg/kg/day. Some patients develop hematological toxicity at relatively low doses and have a modest HbF response, while others tolerate higher doses with a more robust HbF response. Hematological responses to hydroxyurea therapy vary, with HbF levels at MTD ranging from 5 to >30% even for adherent patients. Therapeutic reduction in hemolysis (lower LDH) is also variable though less well described. Our preliminary data suggest substantial inter-individual differences exist in hydroxyurea pharmacokinetics related to drug absorption and disposition, which could affect the laboratory responses and toxicity profile of hydroxyurea therapy for patients with SCA. In Specific Aim 1 we will characterize pharmacokinetic phenotypes of hydroxyurea therapy in children with SCA. We hypothesize that there are two distinct pharmacokinetic profiles for hydroxyurea therapy in SCA, based on time to peak absorption. To test this hypothesis, we will prospectively measure first-dose hydroxyurea pharmacokinetics to document the inter-individual variability and identify distinct phenotypes. In Specific Aim 2 we will investigate the relationships between hydroxyurea pharmacokinetic phenotypes and drug effects. We hypothesize that pharmacokinetic differences can affect the hydroxyurea response, so we will collect prospective pharmacokinetic data from patients with SCA on hydroxyurea therapy whose MTD values have variable % HbF, serum LDH, or MTD values. Distinct response phenotypes for hydroxyurea at MTD have been identified, including high versus low HbF, low MTD, and high LDH despite good HbF induction. In Specific Aim 3 we will investigate the genetic basis for phenotypic variability in hydroxyurea therapy. We hypothesize that specific genetic differences affect the phenotypes observed with hydroxyurea therapy. To test this hypothesis, we will study candidate genes with predicted involvement in the absorption, transport, and metabolism of hydroxyurea, all of which might affect drug pharmacokinetics. Gene loci involved in the cellular effects of hydroxyurea therapy will also be investigated. PUBLIC HEALTH RELEVANCE: The overall goal of this research proposal is to investigate the pharmacological variability of hydroxyurea therapy in patients with SCA, specifically to understand better the inter-individual differences in dosing, toxicity, and laboratory response. The long-term goal is to use information about the pharmacokinetics, pharmacodynamics, and pharmacogenomics of hydroxyurea therapy to help predict the drug effects for individual patients and ultimately to improve medical care for patients with SCA.