A RANDOMIZED, OPEN-LABEL, PARALLEL-GROUP STUDY TO DETERMINE THE PHARMACOKINET

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 假设 这项研究将提供有关美沙拉明及其主要代谢物在接受Asacol治疗轻度至中度活动性溃疡性结肠炎的儿童中的药代动力学信息。我们假设，更深入的美沙拉明在接受该药物的儿童和青少年中的药代动力学分析将有助于更好地理解在该人群中适当和安全的剂量。 具体目标 本研究的主要目的是对5~17岁的溃疡性结肠炎患者口服美沙拉明30 mg/kg、60 mg/kg或90 mg/kg，每12小时分次给药，作为Asacol 400 mg片剂，28天后的药代动力学特征。 次要目标是获得有关5至17岁溃疡性结肠炎患者使用美沙拉明的安全性和耐受性数据。 背景和意义 溃疡性结肠炎是一种以结肠弥漫性、持续性炎症为特征的炎症性肠病。最近的估计表明，美国约有17,000名5至17岁的儿童被诊断为溃疡性结肠炎。1 2 3儿童发病时的平均年龄估计各不相同，但80-90%的患者出现症状时年龄在9岁或以上。 来自医学文献的证据表明，溃疡性结肠炎的临床病程和表现在儿童和成人中是相似的。6 7 8溃疡性结肠炎最一致的症状(腹泻、腹痛、直肠出血、发烧和体重减轻)在儿童和成人中都有类似的比例，而且更依赖于疾病的活动而不是年龄。 Asacol是一种延迟释放片剂，设计用于在pH=7.0的条件下释放美沙拉明(也称为美沙拉嗪)。这种特性导致药物在回肠末端和回肠以外的地方释放。生理因素，如周围介质的pH值，在感兴趣的肠道区域的转运时间，以及吸收和代谢的速度和程度，控制着Asacol药物的释放和释放，这反过来又影响所释放药物的药代动力学。这些生理因素及其对阿萨科尔药代动力学的影响已经在成人中进行了研究，但在儿童中还没有进行相应的研究。然而，描述儿童患者(相对于成人)的胃肠道pH值、转运时间以及药物吸收、代谢和排泄的药代动力学方面的相关研究提供了理由，预期Asacol在儿童人群中的表现特征将与在成人中测量的相似。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. HYPOTHESIS This study will provide information about the pharmacokinetics of mesalamine and its major metabolite in children being treated with Asacol for mildly to moderately active ulcerative colitis. We hypothesize that more in depth pharmacokinetic analysis of mesalamine in children and adolescents receiving this drug will lead to better understanding of adequate and safe dosing in this population. SPECIFIC AIMS The primary objective of this study is to characterize mesalamine pharmacokinetics following 28 days of oral administration of 30 mg/kg, 60 mg/kg, or 90 mg/kg of mesalamine, given in divided doses every 12 hours as Asacol 400 mg tablets, to patients with ulcerative colitis who are 5 to 17 years of age. Secondary objectives are to obtain safety and tolerability data concerning the use of mesalamine in patients with ulcerative colitis who are 5 to 17 years of age. BACKGROUND AND SIGNIFICANCE Ulcerative colitis is a type of inflammatory bowel disease characterized by diffuse, continuous inflammation of the colon. Recent estimates suggest that approximately 17,000 children between 5 and 17 years of age in the U.S. are diagnosed with ulcerative colitis.1 2 3 Estimates of average age at onset in children vary, although 80-90% of patients are 9 years of age or older when symptoms develop. Evidence from the medical literature suggests that the clinical course and manifestations of ulcerative colitis are similar in children and adults.6 7 8 The most consistent symptoms of ulcerative colitis (diarrhea, abdominal pain, rectal bleeding, fever, and weight loss) are found in comparable proportions in both children and adults with the disease, and are more dependent on the disease activity than age. Asacol¿ is a delayed-release tablet formulation designed to deliver mesalamine (also known as mesalazine) at a pH = 7.0. This property results in release of the drug in the terminal ileum and beyond. Physiologic factors such as the pH of the surrounding medium, transit times in the intestinal regions of interest, and the rate and extent of absorption and metabolism govern Asacol drug release and delivery, which in turn influence the pharmacokinetic profile of the delivered drug. These physiologic factors and their effect on Asacol pharmacokinetics have been studied in adults, but corresponding studies in children have not been performed. However, relevant studies describing the gastrointestinal pH; transit times; and pharmacokinetic aspects of drug absorption, metabolism, and excretion in pediatric patients (relative to adults) provide reasons to expect that the performance characteristics of Asacol in the pediatric population will be similar to those measured in adults.