精神障碍儿童、青少年和成人口服利培酮的群体药代动力学。
Population pharmacokinetics of oral risperidone in children, adolescents and adults with psychiatric disorders.
机构信息
Johnson & Johnson Pharmaceutical Research & Development, a Division of Janssen Pharmaceutica NV, B-2340 Beerse, Belgium.
出版信息
Clin Pharmacokinet. 2010 Jul;49(7):465-78. doi: 10.2165/11531730-000000000-00000.
BACKGROUND AND OBJECTIVES
Oral risperidone is licensed globally for the treatment of several psychiatric disorders in children, adolescents and adults. The pharmacokinetic profile of risperidone is well documented in adults. In this study, the pharmacokinetics of oral risperidone in children and adolescents were investigated along with population pharmacokinetics in paediatric and adult subjects.
METHODS
The pharmacokinetics of oral risperidone in children and adolescents were investigated through non-compartmental analysis (paediatric phase I study; n = 24) and population pharmacokinetic analysis using nonlinear mixed-effects modelling software (NONMEM) on a pooled database including both paediatric (n = 304) and adult (n = 476) data. Monte Carlo simulations were performed to evaluate the relevance of the effects of covariates on the plasma exposure of the active antipsychotic fraction.
RESULTS
Non-compartmental pharmacokinetic analysis showed that, after correcting doses for bodyweight, plasma exposure was comparable between children and adolescents and in line with historical adult data. Pooled population pharmacokinetic analysis, using a priori allometric scaling of the clearance and volume of distribution, showed that apparent renal clearance of the active antipsychotic fraction was 0.96 L/h and apparent metabolic clearance was 4.26 L/h for a typical patient weighing 62 kg, aged 18.1 years, with a median creatinine clearance of 117.6 mL/min. For a typical child (11 years, 39 kg), adolescent (15 years, 60 kg) and adult (33 years, 70 kg), the apparent total oral clearance values were 4.35, 5.30 and 5.04 L/h, respectively. None of the tested demographic or biochemical characteristics were found to have a relevant effect on any of the pharmacokinetic parameters of risperidone and the active antipsychotic fraction.
CONCLUSION
Population pharmacokinetics and Monte Carlo simulations demonstrated similar pharmacokinetics of risperidone in children, adolescents and adults.
背景和目的
利培酮口服液在全球范围内被批准用于治疗儿童、青少年和成人的多种精神疾病。利培酮的药代动力学在成人中已有充分的记录。在这项研究中，我们研究了利培酮口服液在儿童和青少年中的药代动力学，并对儿科和成人受试者进行了群体药代动力学分析。
方法
通过非房室分析（儿科 I 期研究；n=24）和使用非线性混合效应模型软件（NONMEM）进行群体药代动力学分析，对包括儿科（n=304）和成人（n=476）数据的合并数据库进行了利培酮口服液在儿童和青少年中的药代动力学研究。进行蒙特卡罗模拟，以评估协变量对活性抗精神病分数的血浆暴露的影响的相关性。
结果
非房室药代动力学分析表明，在按体重校正剂量后，儿童和青少年的血浆暴露与历史成人数据相当。使用清除率和分布容积的先验体表面积比例法进行的群体药代动力学分析表明，对于一个典型体重为 62kg、年龄为 18.1 岁、肌酐清除率中位数为 117.6mL/min 的患者，活性抗精神病分数的表观肾清除率为 0.96L/h，表观代谢清除率为 4.26L/h。对于一个典型的儿童（11 岁，39kg）、青少年（15 岁，60kg）和成人（33 岁，70kg），表观总口服清除率值分别为 4.35、5.30 和 5.04L/h。在测试的任何人口统计学或生化特征中，均未发现其对利培酮和活性抗精神病分数的任何药代动力学参数有显著影响。
结论
群体药代动力学和蒙特卡罗模拟表明，利培酮在儿童、青少年和成人中的药代动力学相似。
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