新生早产儿万古霉素的群体药动学模型

目的 基于非线性混合效应方法建立新生早产儿万古霉素的群体药动学模型,促进个体化用药。方法 回顾性收集170例新生早产儿静脉注射万古霉素(40～60 mg·kg^-1·d^-1)后的275个稳态谷浓度数据及对应的临床信息,建立新生早产儿万古霉素的药动学模型。采用逐步回归法筛选可能影响的协变量,通过统计学相关参数及诊断图形对模型进行拟合优度的评价,并采用自举法和可视化方法验证最终模型的准确性和稳定性。结果 结合异速生长和成熟度公式的一房室模型可较好地拟合万古霉素在新生早产儿体内的过程,表观分布容积和清除率的群体典型值分别为48.0 L·(70 kg)^-1,0.393 L·(70 kg)^-1·h^-1;体质量、矫正胎龄以及肾功能对清除率具有显著性影响;拟合优度、可视化验证及自举法结果表明,模型稳健,参数估算及预测结果可靠。结论 该研究建立的万古霉素群体药动学模型在新生早产儿群体中具有较好的稳定性与可靠的预测效能,可为临床新生早产儿的临床个体化精准用药提供科学依据。     

头孢哌酮钠舒巴坦钠在儿童群体中的药动学研究和剂量优化

目的： 考察头孢哌酮在儿童群体中的药动学特征,促进个体化用药。方法： 收集140例患儿的临床资料和血药浓度数据。采用非线性混合效应模型法建立头孢哌酮在儿童群体中的群体药动学模型,用拟合优度（Goodness-of-fit）、直观预测检验法（VPC）、正态化预测分布误差（NPDE）验证最终模型的预测性能。采用模拟试验评价不同用药方案的合理性。结果： 最终模型评价结果表明模型稳定、预测结果可靠,得到的头孢哌酮药动学参数为：表观分布容积（V_d）0.86 L,清除率（CL）0.38 L·h^-1。模型结构显示患儿的体质量及肾小球滤过率是影响药动学参数的显著性因素。基于此模型最终确定各年龄段儿童的最优给药方案为：针对大肠埃希菌,新生儿患者为30 mg·kg^-1,qid,静滴2 h;1个月~2岁患儿为20 mg·kg^-1,qid,静滴2 h;2~14岁患儿为10 mg·kg^-1,tid,静滴2 h;针对肺炎克雷伯菌,新生儿患者为10 mg·kg^-1,tid,静滴2 h;1个月~2岁患儿为10 mg·kg^-1,tid,静滴2 h;2~14岁患儿为10 mg·kg^-1,bid,静滴2 h。结论： 本研究成功建立了头孢哌酮在儿童患者中的药动学模型,并借此模型推导出不同年龄段患儿针对大肠埃希菌及肺炎克雷伯菌的最佳给药方案。     

拉氧头孢对映异构体在儿童群体中的药动学研究和剂量优化

目的:建立拉氧头孢对映异构体在儿童患者中的群体药动学模型,研究拉氧头孢在儿童患者体内的药动学特点,为拉氧头孢在儿童患者中的个体化用药提供依据。方法:检测145例静脉滴注拉氧头孢患儿的血药浓度,收集患儿临床资料。采用非线性混合效应模型法建立拉氧头孢对映异构体在儿童患者群体中药动学模型,并用自举法、拟合优度图和正态化预测分布误差进行验证。采用蒙特卡洛模拟评价不同给药方案的合理性。结果:四房室模型可以较好描述拉氧头孢对映异构体在儿童患者体内的药动学特征。最终模型稳定,预测结果可靠。拉氧头孢R和S对映异构体的表观分布容积(V_d)分别为5.57 L和4.15 L,清除率(CL)分别为0.78 L·h^-1和1.32 L·h^-1。体质量对拉氧头孢异构体药动学参数有显著影响。结论:该研究成功建立了拉氧头孢对映异构体在儿童患者群体中的药动学模型,可为拉氧头孢的个体化用药提供参考。     

氟康唑片剂在健康人体内的药动学研究

采用高效液相色谱法，对氟康唑在健康人体内的药动学进行了试验研究得出了８ 名男性健康志愿者单剂量口服氟康唑片剂２００ｍ ｇ，后的血清浓度均值与药动学参数均值     

左乙拉西坦儿童生理发育药动学模型的建立和剂量优化

目的:探讨生理发育因素对左乙拉西坦(LEV)在儿童体内药动学特征的影响,评价和优化LEV给药剂量,促进个体化用药.方法:根据203例0.42～15岁癫痫患者的LEV血药浓度及相关临床资料建立群体药动学模型,考察生理发育因素对LEV药动学参数的影响方式和强度.基于模型,模拟和评价不同体质量和年龄段的儿童患者的LEV给药方...     

成人万古霉素群体药动学的研究进展

目的:为临床合理应用万古霉素提供参考。方法:以"成人""万古霉素""群体药动学""群体药动学模型""Adults""Vancomycin""Population pharmacokinetic""PPK model"等为中英文关键词,在PubMed、中国知网、万方等数据库中组合检索自建库起至2019年10月31日发表的相关文献,对成人万古霉素群体药动学(PPK)的研究进展进行综述。结果与结论:共检索到相关文献166篇,其中有效文献25篇。目前已有研究在成年感染患者、危重症患者、接受肾脏替代治疗及血液滤过治疗的患者、神经外科患者、接受体外膜氧合治疗的患者、重症脓毒血症患者、血液肿瘤患者以及下呼吸道感染重症患者等群体中建立了万古霉素PPK模型。成人患者中,肌酐清除率与体质量是影响万古霉素药动学参数的主要因素,提示临床用药时应当关注患者肾功能与体质量;另外,是否感染及感染类型也对万古霉素的药动学参数有不同程度的影响。对于接受肾脏替代治疗及血液滤过治疗的患者,万古霉素的清除主要与其疗法的滤过率相关,提示临床应当根据所接受疗法的滤过率调整剂量;对于神经外科患者,脑脊液白蛋白与脑脊液引流量则是万古...     

去甲万古霉素成人药动学数据外推至儿童群体和剂量优化

目的：获得去甲万古霉素在儿童群体中的药动学特征,优化给药方案以指导临床个体化用药。方法：将成人去甲万古霉素群体药动学（PPK）模型外推得到儿童模型;通过拟合优度图（goodness-of-fit）、可视化预测检验（VPC）及正态化预测分布误差（NPDE）验证外推模型的稳定性和预测性能。采用贝叶斯法获取个体药动学参数,通过蒙特卡洛模拟法评价和优化给药方案。结果：去甲万古霉素在儿童群体中药动学参数的群体均值分别为总体清除率（CL）0.11 L·kg^-1·h^-1、中央室分布容积（V₁）6.08 L、周边室分布容积（V₂）6.21 L、室间清除率（Q）2.32 L·h^-1。拟合优度、VPC和NPDE结果表明外推模型稳定性和预测性能均较好。蒙特卡洛模拟结果提示对于肾功能正常的患儿,去甲万古霉素用于治疗不同MIC（0.25,0.5,0.75和1 mg·L^-1）细菌感染时,要使体内暴露水平的目标获得概率（PTA）达到90%以上,对葡萄球菌属的理想日剂量应分别为16,32和48 mg·kg^-1及以上,对肠球菌属的理想日剂量应分别为16,24,32和40 mg·kg^-1。结论：本研究成功外推得到去甲万古霉素在儿童群体的药动学模型和参数,模拟结果显示,现行去甲万古霉素给药剂量可能偏低。     

中国健康人群西布曲明的群体药动学模型的建立

目的建立中国人群中西布曲明的群体药动学模型。方法 20例男性健康志愿者口服10 mg西布曲明,于服药后0～24 h采集13个采样点采血,采用已验证的HPLC法测定血药浓度。采用非线性混合效应模型（NONMEM）进行群体药动学分析,估算药动学参数。以直观预测检验（Visual predictive check,VPC）和正态预测分布误差（Normalized predictive distribution error,NPDE）,Bootstrap法进行模型性能评估。结果以有吸收时滞的一级吸收和消除的二房室模型为西布曲明的基础药动学模型。协变量筛选未见体重、年龄可显著影响模型参数。残差模型选择指数模型。西布曲明群体药动学参数V1,V2,CL,Q,Ka,Tlag的典型值分别为：7.85 L、2.03 L、1.08 L/h、0.289 L/h、1.95/h、0.187 h;个体间变异分别为42.8%、48.2%、38.5%、27.1%、56.8%和17.8%。Bootstrape、拟合优度、VPC和NPDE的评价结果均表明模型稳定,预测结果可靠。结论用非线性混合效应模型法建立的中国人群中西布曲明的群体药动学模型,结果稳定。     

群体药动学参数的估算与应用

群体药动学参数在给药个体化中,有着极其重要的地位.当病人明确诊断,选定药物后,首先根据群体药动学参数设计给药方案,如果群体代表性强,预报的血药浓度将接近期望值,不然会造成较大的误差。     

用模型和模拟方法设计氨氯地平的群体药动学研究方案

合理的采样设计是建立可靠群体药动学模型的重要基础。应用非线性混合效应模型的群体药动学研究,是一种有效利用稀疏血样数据估算群体药动学参数的方法。本研究根据D最优化设计和贝叶斯法设计采样方案。以已报道的氨氯地平群体药动学模型为基础,根据临床研究的目的、给药方案和随访时间等设计几套采样方案,采用WinPOPT软件计算优化采样方案,用蒙特卡罗法(Monte Carlo)对各优化的采样方案分别建立一套含400个患者的NONMEM数据文件,用NONMEM7.2软件模拟氨氯地平的浓度数据,然后估算其重要药动学参数(CL/F,V/F和Ka),并计算其平均预测误差(MPE)和平均绝对预测误差(MAPE)。在6个采样方案中,以方案6和3对CL/F估算的准确度和精密度较优,MPE分别为0.1%和0.6%,MAPE均为0.7%。对V的估算,各采样方案间无明显差异。因此,选用氨氯地平拟合药动学参数的准确度和精密度较优,且采样点个数较少的方案3为最佳临床研究方案。本研究旨在为开展氨氯地平在肾功能损害合并高血压患者的群体药动学研究提供科学、有效的采样方法,为群体PK/PD研究提供一种优化设计临床研究方案的科学方法。     

A population pharmacokinetic model for docetaxel (Taxotere®): Model building and validation

A sparse sampling strategy (3 samples per patient, 521 patients) was implemented in 22 Phase 2 studies of docetaxel (Taxotere^®) at the first treatment cycle for a prospective population pharmacokinetic evaluation. In addition to the 521 Phase 2 patients, 26 (data rich) patients from Phase 1 studies were included in the analysis. NONMEM analysis of an index set of 280 patients demonstrated that docetaxel clearance (CL) is related to α1-acid glycoprotein (AAG) level, hepatic function (HEP), age (AGE), and body surface area (BSA). The index set population model prediction ofCL was compared to that of a naive predictor (NP) using a validation set of 267 patients. Qualitatively, the dependence ofCL onAAG, AGE, BSA, andHEP seen in the index set population model was supported in the validation set. Quantitatively, for the validation set patients overall, the performance (bias, precision) of the model was good (7 and 21%, respectively), although not better than that of theNP. However, in all the subpopulations with decreasedCL, the model performed better than theNP; the more theCL differed from the population average, the better the performance. For example, in the subpopulation of patients withAAG levels>2.27 g/L (n=26) bias and precision of model predictions were 24 and 32% vs. 53 and 53%, respectively, for theNP. The prediction ofCL using the model was better (than that of theNP) in 73% of the patients. The population model was redetermined using the whole population of 547 patients and a new covariate, albumin plasma level, was found to be a significant predictor in addition to those found previously. In the final model,HEP, AAG, andBSA are the main predictors of docetaxelCL.     

重症感染患者多黏菌素B群体药代动力学模型的外部验证

目的:对既往发表的多黏菌素B群体药代动力学(population pharmacokinetics,PPK)模型进行外部验证,评估各模型对重症感染患者血药浓度的预测性能。方法:在PubMed数据库、Web of Science核心合集、中国知网、万方数据库检索建库至2022年3月公开发表的多黏菌素B PPK模型的相关文献,提取模型结构和参数信息。同时收集南京大学医学院附属鼓楼医院接受多黏菌素B治疗重症感染患者的临床数据作为外部数据集。根据患者是否采用连续肾脏替代疗法(continuous renal replacement therapy,CRRT)分为非CRRT组和CRRT组。利用2组数据对已发表模型进行基于模型预测和模型模拟的评价。结果:检索到14个多黏菌素B PPK模型。CRRT组,预测误差检验结果显示,所有已发表模型均不满足选定的标准。非CRRT组,有一个模型具有较好的血药浓度预测性能。结论:可以尝试利用预测结果良好的模型在非CRRT患者进行前瞻性个体化给药。     

万古霉素在重症监护患者的群体药代动力学模型建立与验证

目的建立适合重症监护患者的万古霉素群体药代动力学模型,用以指导其给药方案调整。方法收集54例重症监护患者的112个常规血药浓度监测数据,用NONMEM软件以非线性混合效应模型进行群体分析,建立单房室药代动力学模型。通过拟合优度评价及自举验证法进行模型的内部验证;收集35例重症监护患者的95个常规血药浓度监测数据,通过拟合优度参数法进行模型的外部验证。以评价最终模型的拟合性能。结果模型内部验证及外部验证的结果表明,模型结构稳定,能较好地预测万古霉素浓度的动态变化规律。结论万古霉素静脉注射给药后的体内过程符合单房室药代动力学的特征,美罗培南对万古霉素的清除率有显著影响。     

Pharmacokinetic aspects of caffeine in premature infants with apnoea

Summary The pharmacokinetics of caffeine was examined in 13 premature infants (gestational age 25–34 weeks, birth weight 920–2060 g, postnatal age 1–42 days) who received the drug for treatment of opnoea. Caffeine (1% aqueous solution) was given i.v. in single doses; guided by the clinical response infants received between one and seven (mean 2.6) doses of 15 mg/kg. Mean (± SE; range) Cl_b was extremely slow − 8.5 ml/kg/h (±0.4; 5.8–12.2), t_1/2 was prolonged − 65.0 h (±3.7; 48.2–87.5 h) and Vd was 0.781/kg (±0.04; 0.47–1.01). No significant correlation was found between Cl_b, t_1/2 and postnatal age in the whole group or in individual infants. Effective plasma concentrations varied over a wide range (12–36 μg/ml) and overlapped with subtherapeutic concentrations (⩽24 μg/ml). Single doses of 15 mg/kg i.v. or p.o. prevented apnoea in most cases, if necessary followed by additional doses. Monitoring the blood level of caffeine in infants receiving frequent repeated doses is necessary to prevent toxicity.     

Pharmacokinetics of fluconazole in people with HIV infection: a population analysis

1 The population pharmacokinetics of fluconazole have been investigated in 113 male subjects with HIV infection and AIDS. Plasma concentration–time data (between 1 and 17 observations per dose) were collected from individuals as part of a pharmacokinetic investigation (13 subjects) or during routine fluconazole therapy (100 subjects) for the treatment or prophylaxis of fungal infection. 2 A one-compartment pharmacokinetic model was used to describe the disposition of fluconazole after oral and intravenous infusion doses. Population pharmacokinetic parameters were generated using the NONMEM and P-PHARM computer programs. 3 The population estimates (calculated using NONMEM) of fluconazole clearance and volume of distribution were 0.78 l h⁻¹ and 47.6 l, respectively. The intersubject variability for these parameters was 41% and 8%, respectively. The model-dependent estimate of the extent of absorption was 0.99 with an intersubject variability of 6%. Mean population estimates generated by NONMEM and P-PHARM were in close agreement. 4 Examination of the relationship between patient covariates and pharmacokinetic parameters indicated that intersubject variability in fluconazole clearance could in part be explained by the severity of disease (as indicated by CD4+T-lymphocyte count) and renal function (indicated by estimated creatinine clearance). Other pharmacokinetic parameters were unaffected by these covariates. 5 Fluconazole clearance (estimated using NONMEM) in subjects with a CD4+T-lymphocyte count less than and greater than 200 cells mm³ was 0.73 l h⁻¹ (95% CI ; 0.64–0.82 l h⁻¹) and 0.99 l h⁻¹ (95% CI ; 0.86–1.12 l h⁻¹), respectively. The regression model for fluconazole clearance that accounted for changes in renal function and disease severity was CL (l h⁻¹)=0.25 (33%)+0.0057 (32%)×CLcr (in ml min⁻¹)+0.00068 (10%)×CD4 cell count (in cells mm⁻³) where intersubject variability (expressed as %CV) is shown in brackets. 6 Based on pharmacokinetic considerations a reduction in the dose of fluconazole would appear to be warranted in people with HIV infection who are seriously ill or who have compromised renal function. However, the emergence of resistance to fluconazole must also be considered when thinking of dosage adjustments.     

替考拉宁国外儿童药动学数据在国内儿童中的外推适用性考察和剂量优化

目的：考察替考拉宁国外儿童药动学数据在国内汉族儿童中的跨种族外推适用性,为临床个体化给药提供参考依据。方法：收集85例国内汉族儿童的监测数据和临床资料,参考已发表的国外儿童替考拉宁药动学模型,采用外推方法获取我国汉族儿童群体的药动学模型,用拟合优度（Goodness-of-fit）、直观预测检验法（VPC）、正态化预测分布误差（NPDE）对最终模型的预测性能进行验证。结果：本研究获取的我国汉族儿童替考拉宁药动学参数为：V₁（中央室分布容积）=（7.83±5.14）L,V₂（周边室分布容积）=（15.13±9.75）L,CL（表观清除率）=（0.32±0.21）L·h^-1,CL₂（周边室清除率）=（0.23±0.11）L·h^-1。拟合优度、直观预测检验和NPDE结果表明,外推模型稳定,预测结果可靠。模拟结果显示,按说明书6 mg·kg^-1,或10 mg·kg^-1,每日一次维持剂量给药,稳态谷浓度很难达到15~30 mg·L^-1的目标浓度范围,维持剂量应提高为15 mg·kg^-1,每日一次。结论：该研究通过模型外推成功获取了替考拉宁在我国汉族儿童群体的药动学参数,模拟结果提示说明书儿童维持剂量偏低。     

Single dose prophylaxis with metronidazole in infants during abdominal surgery: A pharmacokinetic study

Summary Plasma metronidazole was measured following a single interavenous dose of 20 mg/kg (Flagyl 5 mg/ml) in 12 infants less than 1 year of age undergoing abdominal surgery. In all patients sufficient plasma concentrations, well above the MIC values for anaerobic bacteria, were found for at least 16 h. A prolonged half-life was demonstrated in the group less than 8 weeks of age (t_1/2/18.4 h). The group over 8 weeks of age demonstrated a t_1/2 comparable to that seen in adults (t_1/2 7 h).     

Intravenous indometacin in preterm infants with symptomatic patent ductus arteriosus. A population pharmacokinetic study

AIMS: To characterize the population pharmacokinetics of indometacin in preterm infants with symptomatic patent ductus arteriosus and to investigate the influence of various factors on the response to treatment. METHODS: Data were collected from 35 infants (gestational age 25-34 weeks; postnatal age 1-77 days) in neonatal units in Belfast and Copenhagen. Infants received an initial course of up to three doses of intravenous indometacin (0.1-0.2 mg kg(-1)) as considered appropriate by the treating physician. For those infants who did not respond to therapy or in whom the ductus reopened, a second course was sometimes given. Population analysis of the 185 plasma concentrations obtained was conducted using NONMEM and pharmacokinetic and demographic differences between responders and nonresponders were compared. RESULTS: The concentration-time course of indometacin was best described by a one-compartment model. The final population parameter estimates of clearance (CL) and volume of distribution (V) (standardized to the median weight of 1.17 kg) were 0.00711 l h(-1) and 0.266 l, respectively. CL increased from birth by approximately 3.38% per day and V by approximately 1.47% per day. Concomitant digoxin therapy resulted in a 30% decrease in V. Interindividual variability in CL and V was 41% and 21%, respectively. Interoccasion variability for CL was 43%. Residual variability corresponded to a standard deviation of 0.148 mg l(-1). Closure occurred in 75% of infants with a plasma concentration > or = 0.4 mg l(-1) 24 h after the last dose. CONCLUSIONS: Dosing regimens for indometacin should take into account the weight and postnatal age of the infant and any concomitant digoxin therapy. The population estimates can be used to determine typical values of CL and V allowing the prediction of individualized doses of indometacin that should increase the probability of achieving a 24 h plasma concentration > or = 0.4 mg l(-1). Although the pharmacokinetic estimates will be affected by both interindividual and within-individual variation, it is anticipated that this approach will decrease the variability of exposure and optimize treatment outcome.     

Designs for population pharmacodynamics: Value of pharmacokinetic data and population analysis

Analyses of simulated data from pharmacokinetic/pharmacodynamic (PK/PD) studies varying with respect to the amount and timing of observations were undertaken to assess the value of these design choices. The simulation models assume mono- or biexponential drug disposition, andE _max-type pharmacodynamics. Data analysis uses a combined PK/PD population analysis or a hybrid, individual-PK/population-PD analysis. Assuming that the goal of the PK/PD studies is to estimate population PD, performance of designs is judged by comparing the precision of estimates of population mean PD parameters and of their interindividual variability. The simulations reveal that (i) PK data, even in small number (2 points per person from as few as 25–50% of persons) are very valuable for estimating population PD; (ii) designs involving more individuals, even if many are sparsely sampled, dominate designs calling for more complete study of fewer persons; (iii) the population analysis is generally superior to the hybrid analysis, especially when the PK model is misspecified (biexponential assumed to be monoexponential for analysis); (iv) varying sampling times and doses among subjects protects against the ill effects of model misspecification. In general, the results are quite encouraging about the usefulness of sparse data designs to estimate population dose response. Work supported in part by U.S. Department of Health, Education and Welfare, Grants GM26676, GM26691.