Hydroxyurea Pharmacokinetics and Pharmacogenomics

描述(由申请人提供)：羟基脲在儿童和成人镰状细胞性贫血(SCA)中的使用正在增加，但个体间存在显著差异，限制了其作为常规和有效治疗剂的效用。例如，药物剂量变化很大，个别患者的最大耐受量(MTD)在10至35 mg/kg/天之间。一些患者在相对较低的剂量下出现血液毒性，并有温和的HBF反应，而另一些患者则耐受较高剂量，HBF反应更强烈。血液学对羟基脲治疗的反应各不相同，即使对于粘连的患者，MTD时的HBF水平也从5%到30%不等。溶血的治疗减少(较低的LDH)也是可变的，尽管描述得不太好。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差异，这可能会影响羟基尿素治疗SCA患者的实验室反应和毒性。在特定的目标1中，我们将描述羟基脲治疗SCA儿童的药代动力学表型。我们假设，在SCA中，羟基脲治疗有两种不同的药代动力学特征，基于到达吸收峰值的时间。为了验证这一假设，我们将前瞻性地测量首剂羟基脲的药代动力学，以记录个体间的变异性并识别不同的表型。在具体目标2中，我们将研究羟基脲的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可以影响羟基尿素的反应，因此我们将收集羟基尿素治疗SCA患者的前瞻性药代动力学数据，这些患者的MTD值具有可变的%HBF、血清LDH或MTD值。羟基脲在MTD的不同反应表型已被确定，包括高和低HbF，低MTD和高LDH，尽管HbF诱导良好。在特定的目标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会影响羟基脲治疗观察到的表型。为了验证这一假设，我们将研究预测参与羟基脲吸收、运输和代谢的候选基因，所有这些基因都可能影响药物的药代动力学。羟基脲治疗的细胞效应所涉及的基因位点也将被调查。公共卫生相关性：这项研究计划的总体目标是调查羟基脲治疗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疗法的药代动力学、药效学和药物基因组学信息，帮助预测个别患者的药物效果，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.