卡马西平在癫痫患儿中的群体药动学研究

目的:研究卡马西平(CBZ)在癫痫患儿中的群体药动学。方法:回顾性收集我院119例服用CBZ的门诊癫痫患儿的稳态血药浓度(n=122)。用非线性混合效应模型(NONMEM)法进行数据分析,定量考察年龄、性别、体重、日剂量和合用其他抗癫痫药对CBZ清除率的影响。采用一房室开放模型和一级吸收和消除的药动学模型,按照固定吸收速率常数文献值,最终求算CBZ的清除率。结果:最终拟合群体药动学模型为:CL=0.593·(体重/28.5)0.63·日剂量0.569。性别、合用丙戊酸钠不影响CBZ的清除率。结论:用NONMEM法估算CBZ的清除率和推荐剂量,可为临床制订个体化给药方案、提高疗效、降低药物的毒副作用提供依据。     

中国成年癫痫患者奥卡西平活性代谢产物的群体药动学

目的：建立中国癫痫患者奥卡西平活性代谢产物10-羟基卡马西平的群体药动学模型,进而取得对癫痫患者有效的数据参数,为癫痫患者给出有针对性的给药治疗依据。方法：通过实地收集参与研究使用奥卡西平片患者血液药物含量监测数据,利用NLME软件来实现近似群体药动学数学逻辑模型,建立基础模型和统计学模型后,考察年龄、体质量、合并用药等潜在影响10-羟基卡马西平药动学的相关变量参数,将Bootstrap估得的和原始数据估得的参数值进行对比分析,确保模型对实验有效以及测验结果稳定,对建立的模型通过自举法进行验证。结果：共收集了119个患者的180个浓度点,所建立的10-羟基卡马西平的群体药动学模型符合一级吸收、一级消除的一室模型,CL/F及V_d/F群体值分别为1.22 L·h^-1和43.21 L;K_a固定为0.5 h^-1。体表面积对10-羟基卡马西平的清除率有显著影响。结论：初步建立了中国癫痫患者奥卡西平活性代谢产物10-羟基卡马西平的群体药动学模型,为癫痫患者给出了有针对性的给药治疗依据。     

RP-HPLC法测定癫痫患者血浆中奥卡西平血药浓度和药动学研究

目的建立人血浆中奥卡西平药物浓度的RP-HPLC检测方法,并研究其在人体内的药动学。方法采用液–液萃取法,用萃取液甲基叔丁基醚萃取癫痫患者血浆中的奥卡西平后,以阿普唑仑为内标。色谱柱为Kromasil 100A C18(250mm×4.6 mm,5μm),柱温40℃,流动相为甲醇–乙腈–水–磷酸(30∶30∶40∶0.04),体积流量1.0 mL/min,紫外检测波长243 nm,固定进样量20μL。以3p97软件计算10名受试者清晨空腹单剂量口服奥卡西平片600 mg后的平均药动学参数。结果血浆中内源性杂质对样品测定无干扰,奥卡西平在21.6~2 160.0μg/L(r=0.999 2)线性关系良好,最低定量限21.6μg/L;方法回收率为95.45%~107.69%;日内RSD值为4.97%~7.35%,日间RSD值为4.81%~11.27%。含药血浆经3次冻融后稳定性良好。结论本方法操作快速、简便、灵敏度高、准确度好,可用于含奥卡西平血样的即时检测分析和临床药动学研究。     

非线性混合效应模型法估算癫痫患者卡马西平的群体药动学参数

目的:建立癫痫患者卡马西平(CBZ)的群体药动学(PPK)模型。方法:采集我院服用CBZ的270例门诊癫痫患者的稳态血药浓度数据(共316个样本)以及患者相关资料数据。应用非线性混合效应模型(NONMEM)法估算癫痫患者CBZ的PPK参数值,建立PPK模型。并运用自举法(Bootstrap)验证模型的可靠性。结果:年龄(AGE)、每日服药剂量(DKG)、体质量(BW)均为CBZ清除率(CL)的影响因素。最终模型:当AGE≤14岁时,CL(L/h)=[2.55+0.013×(AGE-15)]×(DKG/0.011)0.443×(BW/40)0.392;AGE>14岁时,CL(L/h)=2.55×(DKG/0.011)0.443×(BW/40)0.392。表观分布容积(Vd)=85L。经Bootstrap法验证,本模型稳定、可靠。结论:用NONMEM软件成功建立我院癫痫患者服用CBZ的PPK模型。根据本院癫痫患者的PPK模型,结合患者DKG、BW和合并用药可估算其CL,优化临床个体化用药方案。     

奥卡西平在癫痫儿童患者中的群体药代动力学研究

目的 通过建立奥卡西平的活性代谢产物10,11-二氢-10-羟基卡马西平(MHD)在癫痫儿童患者中的群体药代动力学(PPK)模型,定量考察影响MHD药代动力学参数估算的因素.方法 回顾性收集299例癫痫患儿的449份血药浓度数据,用非线性混合效应法构建PPK模型,通过拟合优度图和自举法评价模型的预测性能.基于最终模型通...     

基于群体药动学的奥卡西平儿童个体化给药模式的建立

目的基于群体药动学(PPK)和贝叶斯原理,建立奥卡西平的癫痫患儿个体化给药工作模式,促进临床合理用药。方法利用已发表的中国癫痫患儿口服奥卡西平后的PPK模型和JPKD-Bayesian软件建立奥卡西平个体化给药的预测模型。运用该模型对100例癫痫患儿进行个体化给药方案设计。患儿按设计方案规律服药2~4周后测定10-羟基卡马西平的稳态血清谷浓度并与模型预测值相比较,计算平均预测误差、平均绝对预测误差、平均相对预测误差、相对预测误差在±20%和±30%内的比例来验证模型的预测性能。结果个体化给药预测模型的平均预测误差为(0.54±2.00)mg·L~(-1),平均绝对预测误差为(1.75±1.09)mg·L~(-1),平均相对预测误差为(3.86±14.56)%,其中分别有78%和96%的血药浓度数据相对预测误差在±20%和±30%以内。血药浓度预测值对实测值的决定系数R2=87.8%。上述验证结果说明模型的预测准确度和精密度均较高。结论本研究成功建立了可用于儿科患者实施奥卡西平个体化给药的预测模型和完整的工作模式,有助于临床合理用药。     

奥卡西平活性代谢产物10，11－二氢－10－羟基卡马西平在成人癫痫患者中的群体药动学及个体化给药的实验研究

奥卡西平是一种前药,在体内代谢为10,11－二氢－10－羟基卡马西平（Monohydroxycarbazepine,MHD）而发挥作用;本文对其在成人癫痫患者中的群体药动学及个体化给药的实验研究概况进行综述。     

RP-HPLC法测定人血浆中奥卡西平浓度及其药动学研究

目的:建立以反相高效液相色谱法测定人血浆中奥卡西平浓度的方法,并研究其药动学。方法:血样经二氯甲烷提取并速浓采缩用后流进样量分时析间,程色序谱,柱紫为外检Hy测pe波rsi长lC为18,2流57动n相m,为柱甲温醇为-205.1℃m,o固l·L定-进1醋样酸量铵为溶5液0(μ用L,H内3P标O为4调地p西H值泮至。约另4以.8)3p-9三7软乙件胺(计60算∶480名∶0受.1)试,流者清晨空腹单剂量口服奥卡西平胶囊300mg后的平均药动学参数。结果:奥卡西平血药浓度在0.0351～2.245μg·mL-1范围内线性关系良好(r=0.9994),最低定量浓度0.0351μg·mL-1;方法回收率为93.48%～107.29%;日内RSD为1.17%～7.54%,日间RSD为5.88%～10.32%。t1/2Ke为(16.93±5.80)h,tma(x5.88±3.00)h,Cma(x0.56±0.38)μg·mL-1,AUC0～48为(12.11±5.76)ng·h·mL-1。结论:本方法灵敏、准确,可用于奥卡西平的临床血药浓度测定及药动学研究。     

非线性混合效应模型法研究卡马西平在癫痫儿童中的群体药动学

目的:考察卡马西平(CBZ)在癫痫儿童中的群体药动学参数。方法:采集我院的866例儿童癫痫患者服用CBZ常规治疗及监测的资料数据,利用Michaelis-Menten一级消除药物动力学模型,非线性混合效应模型程序估算癫痫儿童服用CBZ的群体药动学参数。结果:癫痫儿童卡马西平群体药动学主要参数Ke、Vd、CL在单用CBZ组分别为0.091h-1、0.502L.kg-1和0.046L.h-1.kg-1;性别、身高以及合并氯硝西泮、妥吡酯对CBZ清除率未见明显影响;儿童年龄、体质量、肝肾功能异常以及合并丙戊酸、苯巴比妥、苯妥因为CBZ清除率影响的重要因素,并且均增加CBZ的清除率。结论:根据癫痫儿童的群体药动学模型,结合患儿的年龄、体质量、肝肾功能、服药剂量以及合并用药等资料,估算其清除率,预测患儿体内的药物浓度,制定个体化给药方案。     

基于群体药动学的儿童奥卡西平给药方案优化和漏服药物补救方案研究

目的:建立奥卡西平在儿童群体中的药动学模型,辅助制定个体化给药方案和漏服药物后的补救方案。方法:收集124例4个月~18岁儿童癫痫患者口服奥卡西平后体内主要活性代谢产物羟基卡马西平(MHD)的药物浓度数据和临床资料,采用非线性混合效应建模法建立群体药动学(PPK)模型。应用自举法、预测值校准的直观预测检验(pc-VPC)、正态化预测分布误差检验(NPDE)评价PPK模型的预测性能。基于最终模型参数,模拟不同特征儿童患者的最佳给药方案和不同漏服场景下的补救给药方案。结果:本研究发现奥卡西平在儿童体内的药动学特征符合一级吸收和消除的一房室模型,按标准体质量70 kg成人校正的群体典型值为:吸收速率常数(K_a)=0.83 h^-1,表观分布容积(V_d/F)=16.70 L,清除率(CL/F)=1.92 L·h^-1。体质量是影响V_d/F和CL/F的显著性协变量。自举法、pc-VPC和NPDE检验显示模型预测准度高,稳定性好。模拟结果显示,按本研究推荐的维持方案和漏服后补救方案给药可提高药物浓度的达标概率,保证治疗的安全性和有效性。结论:本研究通过群体药动学研究,制定了不同体质量分层儿童患者的奥卡西平优化给药方案以及漏服药物后的补救方案,可为临床药物治疗决策提供参考。     

Spotlight on oxcarbazepine in epilepsy

Oxcarbazepine (Trileptal, Timox) is structurally related to carbamazepine and has anticonvulsant activity. Studies suggest that the anticonvulsant activity of oxcarbazepine is mediated via the blocking of neuronal ion channels. In patients aged <18 years, the efficacy of oxcarbazepine monotherapy was similar to that of phenytoin in children with partial onset or generalised tonic-clonic seizures in a 48-week trial. Additional supporting findings demonstrated that 43-71% of patients with partial onset, generalised or undetermined epilepsy were seizure free after oxcarbazepine monotherapy (mean dosage 27.7-50 mg/kg/day; duration 1-5 years). In contrast, one small nonblind trial showed more patients treated with oxcarbazepine monotherapy than with carbamazepine monotherapy had recurrent seizures during 16 months of therapy (although the conclusions that can be drawn from this trial are limited). As adjunctive therapy, oxcarbazepine was significantly better than placebo at reducing seizure frequency in children and adolescents with refractory partial onset seizures with or without secondary generalisation: the median percentage change in partial onset seizure frequency was 35% versus 9%, respectively, during 16 weeks of therapy. In noncomparative trials of adjunctive oxcarbazepine (mean dosage of 34.5-56.7 mg/kg/day), 7-11% of patients with partial onset or generalised seizures were seizure free during treatment, and 20-54% had seizure reductions of > or =50%. Oxcarbazepine was generally well tolerated during monotherapy and adjunctive therapy; 2.5% and 10% of patients withdrew from well controlled trials of oxcarbazepine monotherapy and adjunctive therapy. Oxcarbazepine monotherapy was better tolerated than phenytoin and events observed in oxcarbazepine-treated patients were transient. Oxcarbazepine metabolism is largely unaffected by induction of the cytochrome (CYP) P450 system. However, oxcarbazepine can inhibit CYP2C19 and induce CYP3A4 and CYP3A5, thereby interfering with the metabolism of other drugs (e.g. phenytoin). In addition, oxcarbazepine decreases plasma levels of oral contraceptives and alternative contraceptive methods should be used. In conclusion, oxcarbazepine (as both monotherapy and adjunctive therapy) has shown efficacy in the treatment of partial onset seizures in children with epilepsy. Nevertheless, the generally favorable tolerability profile and relatively low potential for drug interactions of oxcarbazepine make it a valuable option in the treatment of childhood epilepsy.     

应用群体药动学模型制订患儿抗癫痫给药方案的药学会诊实践

目的 为优化癫痫患儿卡马西平和丙戊酸给药方案提供参考。方法 药师参与1例脑外伤术后癫痫患儿的药学会诊,总结分析其使用卡马西平和丙戊酸血药浓度异常的原因,应用群体药动学模型为患儿调整给药剂量,并评价笔者团队所建模型的预测能力。结果 患儿病情得到了有效控制。结论 药师应用群体药动学模型优化抗癫痫药物治疗方案,为临床合理用药提供参考。     

羚羊角颗粒联合奥卡西平治疗小儿癫痫的临床研究

目的探讨羚羊角颗粒联合奥卡西平治疗儿童癫痫的疗效。方法选取2017年5月-2019年5月在潍坊市妇幼保健院儿科住院治疗的46例癫痫患儿为研究对象,根据随机数字法将患儿分为对照组（23例）和观察组（23例）。对照组患儿口服奥卡西平片30 mg/（kg·d）,1次/d。观察组在对照组的基础上口服羚羊角颗粒,5 g/次,2次/d。两组均连续服用15 d。观察两组患者的临床疗效,同时比较两组治疗前后的脑电图波段占比情况及血清白细胞介素6（IL-6）、肿瘤坏死因子-α（TNF-α）、基质金属蛋白酶-9（MMP-9）、高迁移率蛋白1（HMGB1）水平。结果治疗后,对照组总有效率为69.57%,显著低于观察组的95.66%,两组比较差异具有统计学意义（P<0.05）。治疗后,两组癫痫发作频率和持续时间均显著降低（P<0.05）;治疗后,观察组发作频率和持续时间显著低于对照组（P<0.05）。治疗后,两组患者脑电图波段δ波、θ波百分比显著降低,而α波、β波百分比显著升高（P<0.05）;观察组患者脑电图波段δ波、θ波百分比低于对照组,α波、β波百分比高于对照组（P<0.05）。治疗后,两组IL-6、TNF-α、MMP-9、HMGB1水平均显著降低（P<0.05）;且观察组患者的IL-6、TNF-α、MMP-9、HMGB1水平显著低于对照组（P<0.05）。治疗期间,观察组患者的不良反应总发生率8.69%,低于对照组的34.78%（P<0.05）。结论羚羊角颗粒与奥卡西平联合治疗癫痫患儿临床的效果显著,可明显控制癫痫发作,减少脑电图中痫性放电,患儿智力水平和生活质量得到提高,在临床上值得推广。     

小儿抗痫胶囊联合奥卡西平治疗小儿癫痫的疗效观察

目的 探讨小儿癫痫应用小儿抗痫胶囊联合奥卡西平片治疗的临床效果。方法 选取2016年1月—2018年8朝阳市第二医院收治的150例小儿癫痫患者,运用随机数字表法将其随机分成观察组（n=75）和对照组（n=75）。对照组患者口服奥卡西平片,以10 mg/（kg·d）为起始剂量,而后每隔1周,增加剂量10 mg/（kg·d）,直至维持剂量30 mg/（kg·d）,均分早晚2次给药。观察组在对照组基础上口服小儿抗痫胶囊,8粒/次,3次/d。连续治疗6个月。对比两组临床疗效,治疗前后癫痫计分、发作频率、持续时间、痫性放电比率、儿童生活质量量表（Peds QLTM4.0）普适型家长代评量表评分及韦氏儿童智力量表第四版（WISC-Ⅳ）评分变化。结果 治疗后,观察组总有效率为93.3%,较对照组81.3%显著增加（P<0.05）。与治疗前相比,两组治疗后癫痫发作情况（包括意识状态及意识障碍、强直、阵挛的持续时间和脑电图）计分及其总分均显著下降（P<0.05）;但观察组减少更显著（P<0.05）。两组治疗后发作频率、痫性放电比率均较治疗前显著降低,而持续时间均显著缩短（P<0.05）;且观察组改善更显著（P<0.05）。两组治疗后Peds QLTM4.0普适型家长代评量表中各维度（生理功能、社交功能、学校表现、情感功能）评分及其总分均较治疗前显著升高（P<0.05）,而观察组上升更显著（P<0.05）。两组治疗后WISC-Ⅳ中各指数（语言理解、知觉推理、工作记忆、加工速度）评分及总智商评分均显著高于治疗前（P<0.05）,且观察组增高更显著（P<0.05）。结论 小儿癫痫应用小儿抗痫胶囊联合奥卡西平片治疗的整体效果显著,可明显稳定患儿病情,控制癫痫发作,减少痫性放电,提高患儿生活质量及智力水平,且安全性较高。     

儿童生理药动学模型及其在儿科用药研究中的应用进展

在儿科用药研究中,儿童生理药动学(PBPK)模型已成为确定首次儿童用药剂量和指导儿童临床试验设计的一个重要方法。本文通过比较PBPK模型和房室模型,并结合既往的经验,重点从发育生理学和细胞色素P450酶的个体发生学等方面阐述儿童PBPK模型的特点,介绍儿童PBPK模型的建模策略、误区及注意事项,同时结合最新的文献实例和FDA审评观点,对其在儿科用药研究方面的前景进行了分析和探讨。     

Evaluation of Bayesian predictability of vancomycin concentration using population pharmacokinetic parameters in pediatric patients

The objective of this study was to evaluate the Bayesian predictability of vancomycin (VCM) pharmacokinetics in Japanese pediatric patients using one-compartment population pharmacokinetic (PPK) parameters, which we reported previously. The validity of the PPK model was evaluated by bootstrap method and cross validation method, and the Bayesian predictive performance was examined. The predictive performance of the PPK model for premature patients was also examined. The cross validation method showed the predictability to be acceptable for practical use, especially for predicting trough concentration using other trough data. However, for the external premature patient data, this PPK model did not seem to be adequate. A theoretical approach using a simulation technique was also examined to evaluate the predictive performance. The results suggested that the predictability at the peak was not necessarily good at all sampling times and the predictability at the trough was better when a later time point was used. The optimal sampling time for prediction of VCM concentration in pediatric patients is discussed.     

儿童生理药代动力学模型及其在儿科药物研究中的应用

生理药代动力学(physiologically based pharmacokinetic, PBPK)模型是预测药物在特殊人群中的药代动力学、药效学和安全性的重要工具。尤其对于儿童这类不易开展临床试验的人群, PBPK模型的应用更是能有效促进儿科药物的开发以及儿童的临床用药。目前, PBPK模型在儿科药物开发中的主要应用有以下几种:临床试验设计、药物相互作用(drug-drug interaction, DDI)的风险评估和儿童给药剂量的确立等。本综述简介了儿童生理药动学模型在儿科药物研究中的优越性,总结了PBPK模型如何实现从成人到儿童的外推,儿童生理药动学模型的理论基础,建模过程及所要注意的重要生理参数,列举了目前PBPK模型在儿科药物研究中的一些应用实例。最后简述了儿童PBPK模型当前的局限性和未来发展方向。     

Glutathione S-transferase polymorphisms are not associated with population pharmacokinetic parameters of busulfan in pediatric patients

High busulfan exposure is associated with increased toxicity, for example veno-occlusive disease, whereas low exposure results in less efficacy such as lower engraftment rates. Despite adjusting dose to body weight, interindividual variability in pharmacokinetics and thus drug exposure remained rather large. In this report, the contribution of genetic polymorphisms in the glutathione-S-transferases (GST) isozymes GSTA1, GSTM1, GSTP1, and GSTT1 to the pharmacokinetics of busulfan is studied retrospectively. Seventy-seven children, undergoing myeloablative conditioning for allogeneic hematopoietic stem cell transplantation, were treated with busulfan (Busulvex) during 4 days, receiving busulfan either in one single dose or dived in four doses every 6 hours. Genetic variants of GSTA1, GSTM1, GSTP1, and GSTT1 were determined by pyrosequencing. Pharmacokinetic parameters were estimated by using nonlinear mixed-effect modeling (NONMEM). Subsequently, a combined population pharmacokinetic-pharmacogenetic model was developed describing the pharmacokinetics of busulfan taking into account the GST polymorphisms. In the presented pediatric population, body weight appeared to be the most important covariate and explained a major part of the observed variability in the pharmacokinetics of busulfan. None of the studied polymorphisms in the genes encoding GSTA1 GSTM1, GSTP1, and GSTT1 nor combinations of genotypes were significant covariates. It was concluded that in children, variability in pharmacokinetics of busulfan could not be related to polymorphisms in GST.     

肥胖人群药代动力学参数的荟萃分析

目的分析肥胖患者药代动力学特征。方法将研究文献中的人群分为肥胖患者组(BMI≥30 kg.m-2)及非肥胖患者组(BMI<30 kg.m-2),对选用的药代动力学参数进行归一化处理,用RevMan 4.2软件进行荟萃分析与评价。结果 2组患者t1/2、CL、Vd和AUC等药代动力学参数存在明显差异。结论肥胖可改变药物的体内处置过程,临床用药应关注患者特殊性,获得最佳疗效。     

Optimal dosage regimen of meropenem for pediatric patients based on pharmacokinetic/pharmacodynamic considerations

A population pharmacokinetic (PK) model for meropenem in Japanese pediatric patients with various infectious diseases was developed based on 116 plasma concentrations from 50 pediatric patients. The population PK parameters developed in this analysis are useful for calculation of the percent time above minimum inhibitory concentration (%T>MIC) and for optimal dosing of meropenem in pediatric patients. After dosing at 20 mg/kg t.i.d. by 0.5-h infusion (approved standard dose for pediatric patients in Japan), the target value of 50%T>MIC was achieved, indicating that 20 mg/kg t.i.d. by 0.5-h infusion is effective for susceptible bacteria. In contrast, for bacteria with higher MICs such as Pseudomonas aeruginosa (MIC ≥ 2 μg/mL), the probability of target attainment of 50%T>MIC was 60.7% at a dose of 40 mg/kg t.i.d. by 0.5-h infusion (highest dose approved for pediatric patients in Japan). The simulations described in this article indicated that 40 mg/kg t.i.d. with a longer infusion duration (e.g., 4 h) is more effective against bacteria with a MIC higher than 2 μg/mL. The predicted probability of target attainment for 50%T>MIC (97.0%) was well correlated not only to the microbiological efficacy rate (97.0%) but also to the clinical efficacy rate (95.9%) in the present phase 3 study.