ABTR06C1 PHARMACOKINETICS OF DAUNOMYCIN IN CHILDREN

ABTR06C1 道诺霉素在儿童中的药代动力学

• 批准号: 7950647
• 负责人: ALBERTO PAPPO
• 金额: $ 0.41万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7950647
• 关键词: 21 year old; Accounting; Acute; Acute Lymphocytic Leukemia; Adult; Adverse effects; Affect; Affinity; Age; Anthracyclines; Antineoplastic Agents; Behavior; Blood; Body Composition; Body Size; Body Surface Area; Body Weight; Body fat; Body mass index; Cardiomyopathies; Child; Childhood; Clinical Research; Complete Blood Count; Computer Retrieval of Information on Scientific Projects Database; Data; Daunorubicin; Diagnosis; Disease Outcome; Dose; Drug Kinetics; Equation; Ethnic Origin; Fatty acid glycerol esters; Frequencies; Funding; Gender; Grant; Hepatic; Individual; Institution; Kidney; Knowledge; Laboratories; Late Effects; Malignant Neoplasms; Measures; Metabolism; Methods; Modification; Myelosuppression; National Health and Nutrition Examination Survey; Non obese; Obesity; Overweight; Patients; Pediatrics; Pharmaceutical Preparations; Pharmacodynamics; Physiological Processes; Plasma Proteins; Race; Regional Blood Flow; Renal function; Reporting; Research; Research Personnel; Resources; Source; Staging; Stomatitis; Therapeutic; Therapeutic Index; Tissues; Toxic effect; Treatment Protocols; United States National Institutes of Health; Weight; base; drug clearance; drug distribution; experience; leukemia; statistics

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. Daunomycin is an anthracycline antineoplastic drug widely used in the treatment of acute lymphocytic leukemia and other malignancies in childhood. Like many anticancer agents, daunomycin has a narrow therapeutic index. Doses of anticancer drugs are usually calculated based on body surface area (BSA) or body weight as a uniform standard. This practice is based on the concept that hepatic and renal function are proportionate to BSA. In most studies, however, variability in overall drug clearance is only partially accounted for by variability in BSA. There is a growing list of drugs for which clearance has been poorly correlated with BSA. In addition, after equivalent BSA-based doses, some patients experience little toxicity while others may show severe toxic side effects. Therefore some have questioned whether normalizing anticancer drug dose to BSA is the optimal method for selecting a dosing regimen in adults. Furthermore, the appropriate dosing of anticancer drugs in patients who are very large or who are obese presents a major therapeutic challenge. There is only scanty data on daunomycin pharmacokinetics in children in general, and no data on the effects of overweight or obesity on the pharmacokinetics of daunomycin in children. This study will characterize daunomycin pharmacokinetics and explore the effect of body mass index and body composition on them. A better understanding of the relationships among body size, body composition, and pharmacokinetics could provide a rational approach to the problem of appropriate drug dosing. HYPOTHESIS We hypothesize that body mass index and body composition, as well as age, gender, and ethnic background, will have an impact on the pharmacokinetic behavior of daunomycin, a widely used anticancer agent, in patients 21 years of age and younger. Our primary aim is to determine the pharmacokinetics of daunomycin in children. Secondary aims are to explore the relationship between body composition (percent body fat) and daunomycin pharmacokinetics in children and to determine whether daunomycin pharmacokinetics are correlated with gender, age, ethnic background, or laboratory parameters of renal or hepatic function or white blood count, in children. SPECIFIC AIMS:Primary 1. To determine the pharmacokinetics of daunomycin in children. Secondary 1. To evaluate the relationship between body composition (percent body fat) and daunomycin pharmacokinetics in children. 2. To determine whether daunomycin pharmacokinetics are correlated with gender, age, or ethnic background in children. 3. To explore in a preliminary fashion possible relationships between pharmacokinetic results and toxicity. 4. To explore in a preliminary fashion possible relationships between pharmacokinetic results and renal and hepatic function and complete blood count (CBC). BACKGROUND AND SIGNIFICANCE: Daunomycin is an anthracycline antineoplastic drug widely used in the treatment of acute lymphocytic leukemia and other malignancies in childhood. Like many anticancer agents, daunomycin has a narrow therapeutic index. Myelosuppression and stomatitis are common acute toxicities. Cardiomyopathy is an important dose-dependent late effect that is being recognized with increasing frequency. Despite its frequent use, however, daunomycin's pharmacokinetics and pharmacodynamics have not been studied systematically in children and very little is known about the relationship between pharmacokinetic parameters and covariates like obesity, body composition, age, gender, or ethnicity. Dosing is empiric, and a rational basis for dose modifications in children who are overweight or obese, in particular, is lacking. This represents a significant gap in our knowledge of the safe and appropriate use of this important agent. Doses of anticancer drugs are usually calculated based on body surface area (BSA) or body weight as a uniform standard. This practice is based on the concept that hepatic and renal functions are proportionate to BSA. In most studies, however, variability in overall drug clearance is only partially accounted for by variability in BSA. There is a growing list of drugs for which clearance has been poorly correlated with BSA. In addition, after equivalent BSA-based doses, some patients experience little toxicity while others may show severe toxic side effects . Therefore some have questioned whether normalizing anticancer drug dose to BSA is the optimal method for selecting a dosing regimen in adults. Furthermore, the appropriate dosing of anticancer drugs in patients who are very large or who are obese presents a major therapeutic challenge. Better understanding of the relationships among body size, body composition, and pharmacokinetics could provide a rational approach to the problem of appropriate drug dosing. The major factors affecting distribution of drugs in the tissues are body composition, regional blood flow, and the affinity of the drug for plasma proteins and/or tissue components. Obese individuals have larger absolute lean body masses as well as fat masses than non-obese individuals; however, their body fat percentage is much more markedly increased . There are data supporting the hypothesis that many physiologic processes involved in the distribution, metabolism, and elimination of drugs may be altered in obese individuals. Obesity has been reported to alter the pharmacokinetics of several anticancer agents 3- 7. For most drugs, however, there are limited data evaluating the potential relationship between body composition and pharmacokinetics or toxicity of specific agents. Furthermore, it is unclear whether it is better to dose obese patients based on actual weight, ideal weight, or some compromise value. In obese patients, calculated drug doses can be as much as 25 to 30% higher if total body weight is used to determine BSA than if ideal body weight is used. An upper limit or "cap" of dosing based on a BSA of 2 - 2.2 m2 is often empirically recommended . Conversely, however, there is concern that patients who are given reduced doses may have a decreased dose intensity of treatment and a worse disease outcome . Obesity is a increasingly common problem . Obesity is currently defined by body mass index (BMI), which is expressed by the equation BMI = weight (in kg)/height2 (in m2). Children with a BMI greater than the 85th and 95th percentiles of the second National Health and Nutrition Examination Survey (NHANES II) are considered overweight and obese respectively. Recent statistics in pediatrics revealed that 24% of children have a BMI greater than the 85th percentile for age and 13% of children have a BMI greater than the 95th percentile for age. Thus it is likely that an increasing number of children diagnosed with leukemia and other cancers are likely to be overweight or obese at presentation. In order to treat these patients optimally it will be critical to understand appropriate dosing of the commonly used anticancer drugs in obese patients. While BMI is the most common measure currently utilized to identify overweight or obese individuals, relatively few studies have been done to evaluate the accuracy of BMI in the assessment of the actual body composition of an individual patient . In children, it may be important to consider maturation stage, race, gender, and distribution of body fat as well as BMI in determining whether children should be considered obese . Therefore an exploration of the relationship between body composition and BMI in children with cancer is warranted.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 道诺霉素是一种蒽环类抗肿瘤药物，广泛用于治疗儿童急性淋巴细胞白血病和其他恶性肿瘤。与许多抗癌药物一样，道诺霉素的治疗指数较窄。抗癌药物的剂量通常以体表面积（BSA）或体重作为统一标准来计算。这种做法是基于肝肾功能与 BSA 成正比的概念。然而，在大多数研究中，BSA 的变异性只能部分解释总体药物清除率的变异性。越来越多的药物的清除率与 BSA 的相关性较差。此外，在接受同等剂量的 BSA 后，一些患者几乎不会出现毒性反应，而另一些患者可能会出现严重的毒副作用。因此，一些人质疑将抗癌药物剂量标准化为 BSA 是否是选择成人给药方案的最佳方法。此外，对于体型巨大或肥胖的患者，抗癌药物的适当剂量 提出了重大的治疗挑战。一般情况下，关于道诺霉素在儿童中药代动力学的数据很少，也没有关于超重或肥胖对道诺霉素在儿童中药代动力学影响的数据。本研究将表征道诺霉素的药代动力学，并探讨体重指数和身体成分对其的影响。更好地了解体型、身体成分和药代动力学之间的关系可以为适当药物剂量问题提供合理的方法。 假设 我们假设体重指数和身体成分以及年龄、性别和种族背景将对 21 岁及以下患者中广泛使用的抗癌药物道诺霉素的药代动力学行为产生影响。我们的主要目的是确定道诺霉素在儿童中的药代动力学。次要目的是探索儿童身体成分（身体脂肪百分比）与道诺霉素药代动力学之间的关系，并确定道诺霉素药代动力学是否与儿童性别、年龄、种族背景或肾功能、肝功能或白细胞计数的实验室参数相关。 具体目标：主要 1.测定道诺霉素在儿童中的药代动力学。 中学 1. 评价儿童体内成分（体脂百分比）与道诺霉素药代动力学之间的关系。 2. 确定柔红霉素在儿童中的药代动力学是否与性别、年龄或种族背景相关。 3. 初步探索药代动力学结果与毒性之间可能的关系。 4. 初步探讨药代动力学结果与肝肾功能和全血细胞计数（CBC）之间的可能关系。 背景及意义： 道诺霉素是一种蒽环类抗肿瘤药物，广泛用于治疗儿童急性淋巴细胞白血病和其他恶性肿瘤。与许多抗癌药物一样，道诺霉素的治疗指数较窄。骨髓抑制和口腔炎是常见的急性毒性。心肌病是一种重要的剂量依赖性迟发效应，人们越来越认识到这一点。然而，尽管其经常使用，但道诺霉素的药代动力学和药效学尚未在儿童中进行系统研究，并且对于药代动力学参数与肥胖、身体成分、年龄、性别或种族等协变量之间的关系知之甚少。剂量是经验性的，特别是对于超重或肥胖的儿童，缺乏调整剂量的合理依据。这表明我们在安全和适当使用这种重要药物方面的知识存在重大差距。 抗癌药物的剂量通常以体表面积（BSA）或体重作为统一标准来计算。这种做法是基于肝肾功能与 BSA 成正比的概念。然而，在大多数研究中，BSA 的变异性只能部分解释总体药物清除率的变异性。越来越多的药物的清除率与 BSA 的相关性较差。此外，在接受同等剂量的 BSA 后，一些患者几乎不会出现毒性反应，而另一些患者可能会出现严重的毒副作用。因此，一些人质疑将抗癌药物剂量标准化为 BSA 是否是选择成人给药方案的最佳方法。此外，对于体型巨大或肥胖的患者，抗癌药物的适当剂量提出了重大的治疗挑战。 更好地了解身体尺寸、身体成分和药代动力学之间的关系可以为适当药物剂量问题提供合理的方法。影响药物在组织中分布的主要因素是身体成分、局部血流以及药物对血浆蛋白和/或组织成分的亲和力。肥胖个体比非肥胖个体具有更大的绝对去脂体重和脂肪质量；然而，他们的体脂百分比却明显增加。有数据支持这样的假设：肥胖个体中涉及药物分布、代谢和消除的许多生理过程可能会发生改变。据报道，肥胖会改变几种抗癌药物的药代动力学 3-7。然而，对于大多数药物，评估身体成分与特定药物的药代动力学或毒性之间潜在关系的数据有限。此外，目前还不清楚肥胖患者是根据实际体重、理想体重还是某种折衷值来服用剂量更好。对于肥胖患者，如果使用总体重来确定 BSA，则计算出的药物剂量可能比使用理想体重时高 25% 至 30%。根据经验，通常建议基于 2-2.2 m2 BSA 的剂量上限或“上限”。然而，相反，人们担心接受减少剂量的患者可能会降低治疗剂量强度和更差的疾病结果。 肥胖是一个日益普遍的问题。肥胖目前通过体重指数（BMI）来定义，其表达方式为BMI = 体重（公斤）/身高2（平方米）。 BMI 高于第二次全国健康和营养检查调查 (NHANES II) 第 85 个百分位数和第 95 个百分位数的儿童分别被视为超重和肥胖。儿科的最新统计数据显示，24% 的儿童的 BMI 高于年龄的 85%，13% 的儿童的 BMI 高于年龄的 95%。因此，越来越多的被诊断患有白血病和其他癌症的儿童可能在就诊时超重或肥胖。为了最佳地治疗这些患者，了解肥胖患者常用抗癌药物的适当剂量至关重要。虽然 BMI 是目前用于识别超重或肥胖个体的最常用指标，但评估 BMI 在评估个体患者实际身体成分方面的准确性的研究相对较少。对于儿童，在确定儿童是否应被视为肥胖时，考虑成熟阶段、种族、性别、身体脂肪分布以及体重指数可能很重要。因此，有必要探索癌症儿童身体成分与体重指数之间的关系。