地高辛中毒病人的临床药物动力学变化

本文对81例心衰病人的地高辛（DG）临床药物动力学资料进行研究，探讨中毒病人与非中毒病ADG临床药物动力学的差异及影响因素。结果中毒组病人的DG药物动力学参数与非中毒组病人存在极显著性差异（P＜0．01）、CL减少37．9％，Vd减少8．3％，T1／2延长43．5％，K减少1／3；给药剂量也应较非中毒病人减少40％，才能确保用药安全。中毒组病人年龄显著高于非中毒病人（P＜0．01），提示DG中毒多发生于老年心衰病人。而中毒组病人的肾功能显著低于非中毒病人（P＜0．01）。相关分析显示，年龄与肾功能、心功能、CL和Vd相关极为显著（P＜0．01），肾功能与DG药物动力学参数、心功能存在显著相关。     

群体药物动力学在个体化给药中的应用进展

目的群体药物动力学(population pharmacokinetics,PopPK)可综合评价药动学在个体间及个体内的各种变异,并应用Bayesian反馈法,较为准确地预测个体的药动学参数。目前群体药动学已广泛应用在治疗药物监测中,以实现临床个体化给药。本文阐述了群体药物动力学的概况,并对群体药物动力学在个体化给药中的应用进展进行综述。     

头孢拉定临床药代动力学研究及个体化给药方案的制订

目的 测定国产头孢拉定静脉滴注人体时药代动力学参数,为制订个体化给药方案服务.方法 8名健康志愿者恒速静滴3.0g国产头孢拉定,测定人体内血药浓度,所得数据经计算机3P87程序拟合处理得群体参数,在此基础上输入病人个体信息,以1或2个实测血药浓度作为参比,应用《临床药动学给药个体化程序》拟合个体参数.结果 药时曲线符合二室开放模型.T_(1/2)β为0.51h v_c=24.02L/kg cl=0.874ml/min结论 临床调整头孢拉定剂量可制订个体化给药方案。     

肾移植患者西罗莫司的群体药动学研究

目的:建立中国肾移植患者西罗莫司的群体药动学模型,为实施个体化用药提供理论支持。方法:选择47名肾移植术后采用西罗莫司+泼尼松+环孢素或他克莫司或霉酚酸酯(MMF)三联免疫抑制治疗的患者为研究对象,回顾性收集47名患者服药后的101个西罗莫司稳态血药浓度及相应的试验室检查数据,运用Winnonmix药动学软件,采用非线性混合效应模型(NONMEM)分析体重、年龄、性别、给药剂量、合并用药、肌酐清除率等对药动学参数的影响。最终模型的验证采用Jackknife法进行内部验证。结果:西罗莫司符合无滞后时间的一级消除动力学一室模型。固定效应结果量子,合用MMF和体重可影响药物清除率。最终模型公式为:CL/F(L·h-1)=11.01×0.14MMF+0.089×W。CL/F和Vd/F的群体典型值分别是11.01L·h-1和3616L,个体间变异分别为62.82%和85.07%。观测值和预测值间的残差(SD)和相关系数(r)分别是1.0ng·mL-1和0.94。结论:所建立的群体药动学模型能较好地估算服用西罗莫司的肾移植患者的个体及群体药动学参数,对指导临床个体化用药具有重要意义。     

苯妥英钠药代动力学实验的临床意义

目的 对苯妥英钠进行药物动力学研究,制定苯妥英钠个体化给药方案.方法 一次性口服给药,多点采样,分光光度法测定血药浓度,绘制时间-血药浓度曲线,用剩余法原理计算动力学参数.结论 根据该患者药代动力学参数,准确制定个体化给药方案,调整所预期的血药浓度.结论 单一患者进行苯妥英钠药代动力学研究,对制定个体化给药方案更具有临床意义.     

微机预测庆大霉素的临床个体化给药方案

本文用微机预测呼吸系统感染病人庆大霉素个体化给药方案,用FPIA法测定庆大霉素血药浓度。26例病人预测的个体化剂量为120±20mg,预测的峰、谷浓度分别为8.41±0.94μg/ml和0.38±0.29μg/ml,与实测值8.01±1.97μg/ml和0.34±0.36μg/ml相比无显著差异(P>0.05)。用Bayesian两点法估算的药动学参数为:消除t_(1/2) 2.68±0.88h,Vd0.2733±0.0594L/kg,总清除率75.19±19.90ml/h.kg。     

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。     

迭代二步法估算阿米卡星的群体药动学参数

目的：用迭代二步法估算阿米卡星的群体药动学参数。方法：收集58例呼吸系统感染病人静脉滴注阿米卡星的临床血药浓度监测数据,用荧光偏振免疫法测定阿米卡星血药浓度。用迭代二步法估算阿米卡星的群体及个体药动学参数。比较性别、年龄、体重、肌酐清除率等因素对药动学参数的影响。结果：性别对药动学参数无影响,CL与CLcr呈正相关,Vd与体重呈正相关。结论：迭代二步法能较好地估算出阿米卡星的群体及个体药动学参数,用于优化给药方案及预测血药浓度可满足临床需要。     

应用Bayes反馈法预测老年患者头孢唑啉的药物动力学参数

为应用Bayes反馈法预测头孢唑啉在老年患者的药物动力学参数及血药浓度,用高效液相色谱法测定头孢唑啉血药浓度,以1、2个实测血药浓度作为反馈,用Bayes反馈法拟合估算老年患者的个体药动学参数,并与非老年患者比较。结果表明,老年组10例的Cl为（60．1&;#177;17．3）ml&;#183;h^-1&;#183;kg^-1,Vd为（0．21&;#177;0．07）L&;#183;kg^-1,t1/2β为（2．6&;#177;0．8）h;非老年组10例分别为（87．6&;#177;34．4）ml&;#183;h^-1&;#183;kg^-1,（0.19&;#177;0.08)L&;#183;kg^-1和（1．5&;#177;0．4）h。两组Cl、t1/2β之间的差异有显著意义（P＜0．05）,Vd之间的差异则无显著意义（P＞0．05）。血药浓度预测值与实测值有良好的相关性（r=0.997)。结论：老年患者随增龄Cl降低,t1/2β延长,而Vd不变。用Bayes反馈法估算的药物动力学参数可用于预测血药浓度及优化个体化给药方案。     

一步法在茶碱个体化给药中的意义

25例哮喘患者一步法得到茶碱的群体药动学参数Ke 0.087±0.022h~(-1),Vd 0.52±0.10L/kg,CL 44.98ml/(kg·h)当取一点稳态谷浓度作Bayes反馈可得到比较准确的个体药动学参数:12例老年COPD患者Ke 0.054±0.011h~(-1),CL 29±5ml/(kg·h)。18例哮喘患者Ke 0.087±0.030h~(-1),CL 45±15ml/(kg·h),两组患者反馈点实测血药浓度与预测血药浓度相关性均为r>0.99(P<0.01),由此可设计出合理的给药方案,并预报可信的血药浓度。     

难治性心衰病人地高辛中毒监测

本文对２５例地高辛中毒的难治性心衰病人进行监测，结果显示有１５例病人表现出不同程度的中毒症状，平均血药浓度为２．９３ｎｇ／ｍｌ；１０例无明显临床中毒表现，平均血药浓度为２．１９ｎｇ／ｍｌ。地高辛临床药动学参数较一般心衰病人有非常显著性差异（Ｐ＜０．０１），Ｔ＿（１／２），延长４４．１％，Ｖｄ减少１６％，ＣＬ减少４０．８％，ＣｒＣＬ减少２４．８％。在地高辛中毒的诸多诱因中，以肾功能和年龄影响最为显著，ＣｒＣｌ和ＣＬ，Ｖｄ存在良好的正相关，年龄和Ｖｄ存在极好的负相关（Ｐ＜０．０１）。     

Evaluation of a Bayesian method of amikacin dosing in intensive care unit patients with normal or impaired renal function

Our study was designed to determine the population pharmacokinetic parameters of amikacin in intensive care unit patients and to develop a Bayesian method allowing individual estimation of pharmacokinetic parameters. A two-stage method was used for estimating the population characteristics of the pharmacokinetic parameters. Calculations of optimum doses and dosing intervals were based on individual parameters. Our results indicate that the Bayesian method is capable of estimating the individual pharmacokinetic parameters with no significant bias and good precision. Individualization of amikacin dosage was assessed 70 times in 52 patients. To determine the predictive performance of the method, observed peak and trough levels were compared with predicted values by computing precision, bias, and correlation. The amikacin dosing method was unbiased and showed a high correlation coefficient (r = 0.962) between measured and predicted drug serum concentrations. No significant differences were found between the predicted and observed peak (17.3 +/- 3.5 and 17.3 +/- 3.8 micrograms/ml, respectively) and trough (2.86 +/- 0.93 and 3.08 +/- 1.41 micrograms/ml, respectively) amikacin serum concentrations. Among the 52 patients, wide variations were observed in the pharmacokinetic parameters (Vd = 0.21-0.50 L/kg; t 1/2 = 1.1-22 h) and the daily doses (2.8-42 mg/kg/day).     

Population pharmacokinetics of digoxin in Japanese patients: a 2-compartment pharmacokinetic model.

OBJECTIVE: To clarify the observed variability of digoxin disposition by performing a population pharmacokinetic analysis in a Japanese population. DESIGN: Retrospective analysis of clinical pharmacokinetic data. PATIENTS AND PARTICIPANTS: Data were obtained from 106 patients with heart failure and atrial fibrillation (43 males and 63 females). METHODS: Digoxin concentrations in serum were measured by fluorescence polarisation immunoassay. Population pharmacokinetic analysis was performed using a 2-compartment open pharmacokinetic model with the computer program NONMEM. RESULTS: 246 serum concentrations were obtained. Final pharmacokinetic parameters were: CL (L/h) = (0.036 x TBW + 0.112 x CL(CR)) x 0.77SPI x 0.784CCB, V1 = 1.83 L/kg, V2 = 22.6 L/kg and Q = 0.629 L/h/kg, where CL is total body clearance, V1 and V2 are the apparent volumes of distribution in the central and peripheral compartments, Q is intercompartmental clearance, TBW is total bodyweight (in kg), CL(CR) is creatinine clearance (in ml/min), SPI = 1 for concomitant administration of spironolactone (and zero otherwise) and CCB = 1 for concomitant administration of calcium antagonists (and zero otherwise). Concomitant administration of digoxin and spironolactone resulted in a 23% decrease in digoxin clearance. Concomitant administration of digoxin and calcium antagonists (diltiazem, nicardipine, nifedipine or verapamil) resulted in a 21.6% decrease in digoxin clearance. CONCLUSIONS: The estimated population parameter values may assist clinicians in the individualisation of digoxin dosage regimens.     

Population pharmacokinetics of doxorubicin, etoposide and ifosfamide in small cell lung cancer patients: results of a multicentre study

AIMS: To determine the population pharmacokinetic (PK) parameters of doxorubicin (Dox), etoposide (Eto) and ifosfamide (Ifo) in small cell lung cancer (SCLC) patients, to assess the potential relationship between those parameters and to estimate the impact of individual morphological and biological covariates on patients' PK parameters. METHODS: Twenty-four patients with either SCLC limited to the thorax or extensive SCLC entered the study. All but one received at least two 3 day courses of the standard AVI (Dox 50 mg m-2 day 1, Eto 120 mg m-2 day 1,2,3, Ifo 2000 mg m-2 day 1,2) regimen. Individual blood samples were collected during each course and data on 47 courses were available. Data were analysed with the NONMEM program. Dox, Eto and Ifo plasma concentrations were studied with multicompartment (3, 2 and 2, respectively) models. Inter-individual and interoccasion (course-to-course) variabilities were estimated. The influence of individual covariates (age, sex, stage of the disease, weight, height, body-surface area, serum creatinine, total protein, LDH, ASAT, ALAT, alkaline phosphatase, gamma-GT, bilirubin) on PK parameters was also assessed. Correlations between individual PK parameters of Dox, Eto and Ifo were explored by using Pearson's correlation coefficient. RESULTS: Multiple data were available for each patient. Dox clearance (CL) and volume of distribution (Vd) were 32.0 l h-1 and 9.3 l (Inter-individual variability: 17.2% and 19.2%). Eto CL (l h-1) and Vd were, respectively, 3.34-0.0083* serum creatinine (micromol l-1) and 6.38 l (interindividual variability: 15.6% and 18.7%). Ifo CL and Vd at day 1 were 5.6 l h-1 and 26.0 l (interindividual variability: 10.1% and 17.2%, respectively). Estimation of course-to-course variability improved the precision of PK models in some cases. No correlation was observed between the respective PK parameters of each drug. Of individual covariates tested, only serum creatinine correlated with Eto CL (r = -0.37, P < 0.001). Self-induction of the metabolism of Ifo was apparent (mean CL increase from day 1 to day 2 : 42%) and individually correlated with the CL value at day 1 (r = -0.61, P < 0.001). CONCLUSIONS: Assessment of potential relationships between individual systemic exposure of chemotherapy and therapeutic endpoints (tumour response, toxicity and survival) will be required to adjust drugs dosages based on individual PK parameters rather than questionable body-surface area. However, all three drugs in the AVI regimen should be monitored simultaneously.     

Population pharmacokinetics of haloperidol using routine clinical pharmacokinetic data in Japanese patients

OBJECTIVE: To clarify the observed variability of haloperidol disposition in patients with psychiatric disorders. DESIGN: Retrospective population pharmacokinetic study. PARTICIPANTS: 218 Japanese patients aged 16 to 82 years who provided 391 serum haloperidol concentrations. METHODS: Routine clinical pharmacokinetic data gathered from patients receiving haloperidol were analysed to estimate population pharmacokinetic parameters with the nonlinear mixed effects model (NONMEM) computer program. RESULTS: The final pharmacokinetic model was CL = 42.4 * (TBW/60)(0.655) * 0.814(AGE> or = 55) * (DOSE/200)(0.236) * 1.32(ANTIEP) and Vd = 34.4 * TBW * 0.336( AGE> or = 65), where CL is total body clearance (L/h), Vd is apparent volume of distribution (L), TBW is total bodyweight (kg), DOSE is daily dosage (microg/kg/day), ANTIEP = 1 for concomitant administration of antiepileptic drugs (phenobarbital, phenytoin or carbamazepine) and 0 otherwise, AGE > or = 55 = 1 for patient aged 55 years or over and 0 otherwise, and AGE > or = 65 = 1 for patient aged 65 years or over and 0 otherwise. Concomitant administration of haloperidol and antiepileptic drugs resulted in a 32% increase in haloperidol clearance. Patients aged 55 years or over showed an 18.6% reduction in clearance, and elderly patients aged 65 years or over showed a 66.4% reduction in apparent volume of distribution. Inclusion of terms for the concomitant administration of haloperidol and antiparkinsonian drugs (amantadine, bromocriptine, biperiden, trihexyphenidyl or mazaticol) or cytochrome P450 (CYP) 2D6 substrates (levomepromazine, perphenazine, thioridazine, amitriptyline or clomipramine) did not significantly improve the estimate of haloperidol clearance. CONCLUSION: Application of the findings in this study to patient care may permit selection of an appropriate initial maintenance dosage to achieve target haloperidol serum concentrations, thus enabling the clinician to achieve the desired therapeutic effect.     

Animal Pharmacokinetics and Interspecies Scaling from Animals to Man of Lamifiban,a New Platelet Aggregation Inhibitor

Relating pharmacokinetic information obtained in animal species to man (interspecies scaling) can play an important role in enabling understanding of the differences and similarities between species, and helping to predict the kinetic profile of a new compound in man. Interspecies scaling techniques have been applied to lamifiban (Ro 44–9883), a new selective and potent nonpeptidic inhibitor of human glycoprotein IIb-IIIa intended for use in clinical treatment of, for example, acute coronary syndrome. The pharmacokinetic profile of lamifiban in man was predicted from animal data (in rats, dogs and cynomolgus monkeys) by using allometric scaling and concentration-time transformations. These extrapolations for lamifiban were performed prospectively, to help design the first pharmacokinetic studies in man. The approach based on equivalent time was preferred for our prospective predictions, in view of the high values found for the allometric exponents. Using allometric scaling, clearance (CL), half-life(t1/2) and volume of distribution (Vd) were overestimated by approximately two-to fourfold. Compared with allometric scaling, the transformation based on equivalent time improved the prediction for all human pharmacokinetic parameters. For t1/2 and CL, the observed values for man were within the range predicted from the various animal species. Of the individual animal species, the cynomolgus monkey gave the most reliable predictions of these two parameters, as well as accurately predicting the Vd value.     

Clinical pharmacokinetics of phenobarbital in neonates.

Demographic and clinical pharmacokinetic data collected from term and preterm neonates who were treated with intravenous phenobarbital have been analysed to evaluate the role of patient characteristics in pharmacokinetic parameters. Significant relationships between total body weight (TBW) or body surface area (BSA) and volume of distribution (Vd) and total body clearance (CL) were found. Coefficients of determination were: 0.55 and 0.59 for Vd, and 0.76 and 0.72 for CL against TBW and BSA, respectively. In addition, significant relationships between height of the infants and volume of distribution of phenobarbital and total body clearance were observed. Coefficients of determination were 0.58 for Vd and 0.56 for CL. A weaker but significant correlation existed between gestational age and Vd or CL of phenobarbital. Coefficients of determination were 0.43 and 0.64, respectively. There was no correlation between volume of distribution per kg body weight or total body clearance per kg body weight and any patient parameter investigated. However, these latter pharmacokinetic parameters tended to decrease with increasing gestational age and height of the neonates. The results obtained were used to develop new loading and maintenance doses for phenobarbital in neonates based on total body weight and body surface area and based on height and gestational age for cases that weight is not available.     

Re-examination of digoxin dosage regimen: comparison of the proposed nomograms or formulae in elderly patients.

1 Comparison of measured trough serum digoxin concentrations (SDC) with those predicted at steady-state by forty sets of previously described pharmacokinetic equations in conjunction with either measured or estimated creatinine clearance (Clcr) was made in an elderly group of patients with varying Clcr (25-89 ml/min) who received maintenance digoxin therapy. 2 Mean values of day-to-day variation (% coefficient of variation) for serum creatine and measured Clcr examined three times within a week in 7 of 40 elderly patients were 6.42 and 8.36% respectively, while this value for SDC was 12.46%. 3 There was a statistically significant correlation (r = 0.72 to 0.79, P less than 0.001, n = 40) between measured Clcr and that estimated from three different methods. Siersbaek-Nielsen's nomogram approach gave the best correlation. 4 The calculated correlation coefficient values between measured and predicted SDC lay within a relatively narrow range but were weak (r = 0.443-0.628). Prediction error analysis, however, allowed us to determine the best set of pharmacokinetic equations for a first approximation to appropriate digoxin maintenance dosage requirements, namely Gault-estimated elimination rate constant, measured Clcr, and Jusko-estimated volume of distribution.     

Pharmacokinetic study of the digoxin-acenocoumarol interaction in rabbits

A study was carried out to evaluate the potential pharmacokinetic interaction between digoxin and acenocoumarol. The binding of digoxin to rabbit cardiac tissue homogenates was assessed in vitro, using the equilibrium dialysis technique. An increase in the first-order constant (p<0.05) and a reduction in the partition coefficient in the equilibrium situation (p<0.001) of digoxin were observed when the cardiac homogenates were previously treated with acenocoumarol. In the in vivo study, the kinetics of digoxin administered in single and multiple dosage regimens were compared in control rabbits and in rabbits treated simultaneously with acenocoumarol. Kinetic analysis of the results was performed using Non-linear Mixed Effects Modeling (NONMEM). In the presence of acenocoumarol, the population distribution volume (Vd) of digoxin was increased by 40-60%, no differences being found as regards the elimination clearance. Also, joint administration of both drugs led to a reduction in digoxin concentrations in the heart (p<0.01) at the end of the dosage regimen. Both sets of results point to the hypothesis of a hitherto unreported possible pharmacokinetic interaction between the two drugs affecting the distribution process. This interaction could lead to lower plasma digoxin levels, in view of the increased Vd, and a possible reduction in the therapeutic effect, owing to the decrease in affinity and in concentration in heart tissue.