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.
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