地高辛在新生儿和小婴儿中的群体药动学研究

发布时间：2018-03-27 08:56

本文选题：地高辛　切入点：新生儿　出处：《复旦大学》2014年硕士论文

【摘要】：地高辛是一种强心苷类药物,临床中广泛应用于治疗儿童慢性心功能不全和控制快速性心房颤动。由于地高辛治疗指数低,临床使用时需要常规进行治疗药物监测。儿童使用地高辛后,血药浓度个体差异大,该差异与药物的体内处置过程和儿童本身的生理发育特点有关。地高辛主要以原型经肾脏排出体外,儿童的脏器功能(如肾脏等重要的药物体内处置器官)处于不断生长发育过程中。通常,肾单位的数量在妊娠36周已达成人水平,但肾单位的功能发育却持续整个妊娠过程和生命早期。新生儿肾脏功能仍未成熟,在新生儿出生后几个月内,肾血流量增大、肾小球滤过和肾小管分泌、肾小管重吸收能力增强,肾脏功能发育显著,肾排泄能力不断提高,肾功能在1岁左右接近成人水平。1岁以下儿童中,基于体重或体表面积线性的剂量折算将导致地高辛给药存在不足或超量,需要研究地高辛在该年龄段的人群内的代谢,获得该人群患儿地高辛特有的药代动力学参数,减小地高辛的临床用药风险。由于伦理因素的限制,在低年龄儿童中进行频繁多次采样将对患儿的生理和心理带来伤害,因而在低年龄儿童中进行传统药动学研究受到限制,导致大量新生儿及小婴儿的治疗数据缺乏。近年来群体药动学已经开始应用于临床治疗学领域的研究,该方法可分析富集或稀疏的数据组,评价各固定效应因素,随机效应因素对群体统计模型的影响。因而本研究采用非线性混合效应模型法建立中国新生儿和小婴儿儿童地高辛的群体药动学模型,旨在优化地高辛的给药方案。目的:使用地高辛临床血药浓度监测数据研究影响新生儿和小婴儿地高辛体内处置的影响因素,为地高辛的临床个体化给药提供依据。方法：本研究纳入了107名复旦大学附属儿科医院2011-2012年度一岁以下住院患儿地高辛的临床血药浓度监测数据(共计125个采血点),采用非线性混合效应模型法,一级速率吸收和一房室模型建立群体药动学模型。本研究拟考察体重(异速生长模型),日龄,血肌酐,性别,是否合并充血性心衰,合并用药对患儿地高辛清除率和表观分布容积的影响。模型的内部验证采用自取法(bootstrap法),直观预测性检验(visual predictive check, VPC)和正态预测分布误差(normalized prediction distribution error, NPDE)验证模型的稳定性和可预测性：外部验证纳入了24名患儿来评价模型的外推效果。结果：地高辛最终模型清除率和表观分布容积的群体典型值分别为0.147L/h/kg和15.7 L/kg,体重和月龄显著影响地高辛的清除率,同时体重也是影响地高辛表观分布容积的显著变量。建模过程中,吸收速率常数固定为0.718 h-1。Bootstrap参数自取成功率为92.9%,最终模型参数估测值与bootstrap参数中位数无显著性差异,表明模型的稳定性符合要求。直观预测性检验和正态预测分布误差检验表明模型的预测性符合要求。此外,模型的外部验证也符合要求。结论：本研究建立的新生儿和小婴儿地高辛群体药动学模型稳定,可预测,可为地高辛临床个体化给药提供依据。
[Abstract]:Digoxin is a cardiac glycoside drugs in the treatment of children with chronic heart failure and control of rapid atrial fibrillation is widely used in clinical. Digoxin has low therapeutic index, clinical use requires routine therapeutic drug monitoring. The use of digoxin in children, the blood concentration of individual differences, the differences in physiological and drug in the disposal process and children's developmental characteristics. Digoxin with prototype excreted through the kidneys, organ function of children (such as kidney and other important organs of drug disposition) is constantly in the process of growth and development. Usually, the number of nephrons has reached the adult level at 36 weeks of gestation, but nephron function development continued throughout gestation and early life. Yet the neonatal kidney function mature, in a few months after birth, increased renal blood flow, glomerular filtration and tubular secretion, renal tubule Heavy absorption ability, kidney function development significantly, renal excretion ability to continuously improve renal function in children under the age of 1 years old is close to the.1 level in the adult body weight or body surface area, dose conversion based on linear will lead to insufficient or excessive drug digoxin, metabolic needs of digoxin in the age group. To obtain the population pharmacokinetic parameters of digoxin with unique clinical medication, reduce the risk of digoxin. Due to ethical constraints, frequent sampling to the child's physical and psychological harm to children at a young age, so the research is limited in the traditional medicine of low age children, resulting in the treatment of large amounts of data the lack of newborns and small infants. In recent years the population pharmacokinetic studies have begun to clinical application field, this method can analyze enrichment or sparse data sets, evaluation The price of the fixed effect factors, random effect factors on population statistics model. Population pharmacokinetic model of this study using nonlinear mixed effect model was established Chinese neonates and infants with digoxin in children, in order to optimize the digoxin dosage regimen. Objective: clinical effects of digoxin blood concentration monitoring data of neonates and infants effects of digoxin disposition factors for clinical individualized digoxin administration provides the basis. Methods: This study included 107 patients in Paediatrics Hospital Affiliated to Fudan University in 2011-2012 under the age of a hospital with digoxin clinical blood concentration monitoring data (a total of 125 sampling points), using nonlinear mixed effect model, first-order rate and absorption compartmental model establishment of a population pharmacokinetic model. This study intends to investigate the weight (allometric model), age, gender, blood creatinine, is Not with congestive heart failure, combined effects of removing rate and apparent volume of distribution of children with digoxin. Internal validation model using self method (bootstrap method), direct predictive test (visual predictive, check, VPC) and normal distribution prediction error (normalized prediction distribution error, NPDE) and can verify the stability of model prediction: the extrapolation results external validation included 24 children to evaluate the model. Results: the final model of digoxin clearance and apparent volume of distribution of the population values were 0.147L/h/kg and 15.7 L/kg, body weight and month age significant effect of digoxin clearance, while the weight is a significant variable with the apparent volume of distribution. In the process of modeling, the absorption rate constant of 0.718 h-1.Bootstrap parameters to the success rate was 92.9%, the final estimation of the model parameter values and parameters in bootstrap There is no statistically significant difference, indicate that the stability of the model meets the requirements. Direct predictive tests and normal distribution test showed that the prediction error prediction model to meet the requirements. In addition, the external validation model can meet the requirements. Conclusion: This study established the neonates and infants with digoxin population pharmacokinetic model is stable and predictable, but for digoxin clinical individualized medication provides the basis.

【学位授予单位】：复旦大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R969.1

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