NONMEM法分析肾移植患者环孢素A的群体药动学

用HPLC和FPIA法(单克隆抗体)测定全血中环孢素A(CsA)浓度,收集临床60例肾移植患者牛奶送服CsA后浓度数据281点,应用NONMEM程序一步法估算其群体药动学参数,并定量地分析体重、年龄、性别,长期用药对清除率的影响。按口服吸收一室开放模型估算的群体药动学参数为:清除率CL(L·h^-1)、表现分布容积V_d(L)和口服吸收速率常数K_a(h^-1)分别等于59.8,227及1.28,其个体间变异Q_CL(%),Q_VL(%)及Q_Ka(%)分别为30.27,29.02和75.10,浓度观察值与模型预测值的残差变异Q_E(%)等于31.19固定效应与CL的定量关系为:以体重的0.03倍加法调整,男性较女性患者增加4.31,长期用药患者下降12.7。     

何首乌有效成分二苯乙烯苷的药代动力学研究

目的建立小鼠和兔血浆中二苯乙烯苷浓度的HPLC测定方法,研究何首乌中二苯乙烯苷在小鼠和兔体内的药代动力学行为。方法用Diamonsil^TM C₁₈色谱柱(250 mm×4.6 mm,5 μm),以乙腈-甲醇-1%甲酸(15∶18∶67)为流动相,流速1.0 mL·min^-1,检测波长320 nm。结果线性范围为0.41～42.0 μg·mL^-1(γ=0.9999),最低检测浓度为0.051 μg·mL^-1。高、中、低3种不同浓度的平均回收率分别为97.98%,101.7%和104.5%,日内精密度RSD分别为8.7%,2.9%和5.5%。小鼠和兔iv二苯乙烯苷后药代动力学行为均符合二室模型,药代动力学参数分别为:T_1/2α=1.9,2.7 min;T_1/2β=8.3,13.5 min;K₂₁=6.6,4.2 h^-1;K₁₂=3.8,3.0 h^-1;K₁₀=16.0,11.2 h^-1;V_c=0.090,0.198 L·kg^-1;AUC=6.918,4.530 mg·h·L^-1;CL=1.445,2.208 L·h^-1·kg^-1。小鼠ig给药后二苯乙烯苷在胃肠道内的吸收不规则,且血药浓度很低,药代动力学行为不符合房室模型。结论建立了二苯乙烯苷血药浓度的HPLC测定方法,阐明了二苯乙烯苷的药代动力学特征。方法的专属性高,操作简便,结果准确。     

卡维地洛人体药动学与药效学结合模型研究

采用间接药效学模型和效应室模型两种药效学模型分别进行卡维地洛药动学与药效学关系研究, 比较两种药效学模型的拟合程度。高效液相色谱法 (荧光) 测定20名健康志愿者单次口服20 mg卡维地洛片后卡维地洛经时血药浓度, 以DAS 2.0实用药动学计算程序计算卡维地洛药动学参数。同时测定给药前后动脉收缩压和舒张压, 计算降压效果。卡维地洛片主要药动学参数t_1/2为 (4.56 ± 2.56) h, C_max为 (46.29 ± 21.07) ng·mL^-1, AUC_0-∞为 (173.76 ± 87.36) ng·mL^-1·h。间接药效模型主要参数K_in为 (0.41 ± 0.31) % h^-1, K_out为 (0.40 ± 0.26) h^-1, IC₅₀为 (24.40 ± 21.10) ng·mL^-1, AUE为 (3.82 ± 1.46) % h。效应室模型主要参数K_e0为 (0.35 ± 0.27) h^-1, EC₅₀为 (24.30 ± 24.30) ng·mL^-1, AUE为 (5.65 ± 2.54) % h。该方法可用于卡维地洛片人体药动学研究。由AIC值可知, 效应室模型可更好的应用于卡维地洛药动学-药效学结合研究。

     

十名志愿者口服维拉帕米缓释片药代动力学和心电图研究

对10名男性受试者单剂量po240mgVer缓释片药代动力学及心电图变化进行研究。血药浓度—时间数据用零级吸收过程的一室模型拟合,其药代动力学参数:T_max5.9±1.6h;C_max118.9±37.2μg·L^-1;T₁ 5.4±1.5h;k₀30.5±17.5μg·L^-1·h^-1;T_1/210.8±4.9h。PR间期延长有显著意义,血药浓度与PR间期变化满足S 型模型,其药效学参数:EC₅₀ 64.6±16.9μg·L^-1; E_max54±11ms;s 1.68±0.66。     

新生儿庆大霉素的群体药代动力学模型及其预测血药浓度能力的评价

目的　建立庆大霉素的群体药代动力学模型并考察该模型预测血药浓度的能力。方法　收集常规血药浓度监测中的30例新生儿80对庆大霉素血药浓度时间数据进行分析;根据Sheiner等提出的群体药代动力学思想,编制估计群体参数和个体参数的程序,目标函数最小值以MonteCarlo算法求得;预测能力通过计算ME和RMSE来考察。结果　新生儿庆大霉素的群体药代动力学参数分别为:k_e:0.22±0.022h^-1 ,V_d:0.51±0.06L·kg^-1,Cl:112±10mL·h^-1·kg^-1;群体分析组和预测组的预测血药浓度与实测值显著相关(γ=0.920和0.946 ) ;预测组ME和RMSE分别为0.001mg·L^-1 和0.84mg·L^-1 。结论　该模型能较好地预测新生儿庆大霉素的血药浓度。     

NONMEM法估算中国癫痫患者苯妥英的群体药动学参数

临床上常规收集的161例门诊癫痫患者苯妥英(DPH)的每日剂量—稳态血药浓度数据258对,应用NONMEM程序一步估算其群体药动学参数(meansand、variances),并定量地分析体重、性别、合并用药对最大消除速率V_m(mg·d^-1),年龄对米-曼氏常数Km(μg·ml^-1)的影响。异性间DPH的V_m无显著差异,群体特征病人(体重60kg,年龄≥15a,未合并用苯巴比妥、安定或硝基安定)的V_m为439mg·d^-1,K_m为6.21μg·ml^-1。体重对V_m的调整值为WT/60的0.57次方,合并用药时V_m增加8.4mg·d^-1,年龄<15a则K_m下降7%。     

3H羟基斑蝥胺的药物代谢动力学研究

将氚标记的羟基斑蝥胺在大鼠体内研究了药物代谢动力学。所得血药浓度-时间数据依一定程序在709电子计算机上拟合曲线,并计算有关参数。结果表明,静脉注射后符合二房室开放型模型,其药代动力学参数为:t1/2α0.067hr,t1/2β2.208hr,V_d(面积)1.237l/kg,V₁0.264l/kg,K_el1.470 hr^-1,清除率0.388l/hr/kg。灌胃后可以单室开放型模型描述,其药代动力学参数为:K_α2.990hr^-1,K_el0.257hr^-1,V_d1.603l/kg,t1/22.693hr,t_max0.90hr,C_max0.745μg/ml,F94.15%。尚将本药以静脉和灌胃两种途径给药后直接观察在大鼠体内的组织分布和在尿粪胆汁中的排泄,结果表明本药分布广,主要经肾排泄,且排泄较快,与药代动力学分析结果相一致。     

氯氮平在中国精神分裂症人群的群体药物动力学研究

本研究旨在考察口服氯氮平 (clozapine) 在中国精神分裂症患者中的群体药物动力学特征, 探讨各项动力学参数与人口统计学因素及CYP1A2酶基因多态性的关系, 通过建立群体药物动力学模型指导临床个体化给药。研究中采集了临床服用氯氮平的183例精神分裂症患者的626份稳态血样本资料, 随机分组为建模组 (168例) 和外部验证组 (15例)。用非线性混合效应模型 (NONMEM) 程序中的一级评估法 (first-order estimation, FO) 对建模组的数据进行分析, 估算清除率 (CL/F)、表观分布容积 (V/F) 和吸收速率常数 (K_a) 的群体值, 并且定量评价人口统计学指标和CYP1A2酶基因型因素对药物动力学参数的影响。建模中单室一级吸收和消除模型能够较好地拟合数据。最终模型包含了经体表面积归一化的单日剂量 (DBSA) 和吸烟 (SMOK) 因素对CL/F的影响。CL/F (非吸烟组)、V/F和K_a的群体典型值分别为28.5 L·h⁻¹ (5.05%)、1 290 L (16.7%) 和2.26 h⁻¹ (fixed), 相应的个体间变异分别为42.2%和10.0%。研究发现吸烟组的清除率有所上升。观测值与预测值之间的残留误差SD为45.8 μg·L⁻¹。     

前列腺素E1经不同途径给药后的大鼠体内药效学比较

本文研究了前列腺素E₁(PGE₁)分别经不同途径给药后的大鼠体内药效学，旨在寻找目前PGE₁注射给药的替代途径。以PGE₁降压效应作为药效学指标，以静脉注射为对照，分别测定PGE₁经鼻腔、舌下、肌肉(im)、腹腔(ip)给药后的药效学参数，包括峰效应时间(Tmax)，血压下降最大百分数(Emax，%)，效应持续时间(T_d)以及血压下降百分数-时间曲线下面积(AUC，%·min)。研究结果表明，PGE₁经上述途径给药后，药效学参数Emax，T_d，AUC等均随给药剂量的增加而增大，提示存在明显的剂量-效应关系。根据所测Tmax值，推断上述给药途径其吸收速率的大小顺序为：鼻腔≈im>ip>舌下；依据所测药理生物利用度(PF)值，预测药物绝对生物利用度的顺序为：鼻腔>im≈ip>舌下。上述研究结果提示，PGE₁经鼻腔与舌下黏膜给药，有望替代目前的注射给药。     

常咯啉在实验性心律失常狗的药代动力学-药效动力学分析

用Harris冠脉结扎法诱发的心律失常狗研究常咯啉药代动力学-药效动力学。7只狗按83.33μg·kg^-1·min^-1静脉滴注60min,在给药期间和停药后不同时间记录ECG及测定血药浓度。C-T数据用药代程序计算药代参数;药效数据用药代-药效同步分析模型计算药效动力学参数,K₁₀, T_1/2,Vd,Cl分别为0.0087min^-1,78.03min,40.55ml·kg^-1和0.421ml·kg^-1·min^-1;K_eO和Ce(50)分别为0.0048min^-1和2.01μg·ml^-1.     

Novel Pharmacokinetic Modelling of Transdermal Nitroglycerin

Purpose. To construct a pharmacokinetic (PK) model and to determine population PK parameters of nitroglycerin (GTN), 1,2-dinitroglycerin (1,2-GDN), and 1,3-dinitroglycerin (1,3-GDN). Methods. Data were obtained in thirty healthy volunteers following a single dose of a GTN reservoir transdermal patch. Blood samples were obtained just before and at 0.5, 1, 2, 3, 4, 6, 8, 12, 14, and 24 hours after the patch application and 1 hour after its removal. GTN, 1,2-GDN, and 1,3-GDN concentrations were determined using HPLC and simultaneously best fitted using a first-pass mixed-order release one-compartment PK model. Individual estimates (ADAPT-II) were used as priors for a population PK analysis (IT2S). Fitted parameters included the percentage (A) of the nitroglycerin dose reaching the systemic circulation that was released from the patch by a first-order process (K₁); two absorption (ka₁ and ka₂), two metabolite formation (k_fl and k_f2) and one metabolite elimination (k(m)) rate constants; and three volumes of distribution Vc/F, V₂/F and V₃/F. Results. Nitroglycerin mean population parameter estimates and inter-individual variability (CV%) were: A 35% (65), K₁, 0.06 h^–1(91), ka₁ 5 h^–1(46), ka₂ 0.47 h^–1 (39), k_f1 11 h^–1(42), k_f2 0.6 h^–1(34), k(m) 1.4 h^–1(29), V_c/F 6 L(31), V₂ /F 73 L(34), and V₃ /F 23 L(29). The average elimination half-lives for GTN and the two metabolites were 5 and 32 minutes, respectively. Conclusions. The proposed PK model fitted observed concentrations of GTN, 1,2-GDN and 1,3-GDN very well. This model should be useful to predict drug and metabolite concentrations and to assess bioequivalence of two transdermal formulations.     

中国成年患者万古霉素群体药动学研究

目的:利用万古霉素治疗药物监测(TDM)数据建立群体药动学(PPK)模型,用于估算个体化药动学参数。方法:选择使用万古霉素成年患者,详细记录用药、TDM数据以及病理生理资料。采用非线性混合效应模型(NONMEM)法建立万古霉素群体药动学模型。结果:169例患者数据来源于血液科及重症监护(ICU)病房等9个科室,共获得385个血药浓度数据,其中峰浓度39个,谷浓度346个。根据文献资料及TDM数据建立二室PPK模型,万古霉素清除率(CL)、中央室(V1)及外周室(V2)分布容积、室间清除率分别为4.08 L·h-1、21.7 L、65.3 L、5.95 L·h-1,患者肌酐清除率及体重分别对CL及V2具有显著影响。根据模型预测169位患者AUC0-24h为(450.1±231.8)mg·L-1·h。结论:本研究建立的万古霉素PPK模型可以用于中国成年患者个体化药动学参数估算。     

安定在家兔体内的肠胃循环药代动力学分析

6只家兔iv安定5 mg·kg^-1后,浓度—时间数据呈现双峰形。本文提出肠胃循环动力学模型,用于分析实测数据,得到了一般动力学参数:T_1/2(α)=0.21±=0.15 h,T_1/2(β)=2.2+0.6 h,K_e=1.5±0.6 h^-1,K₁₂=2.0±1.0 h^-1,K₂₁=1.0±0.4 h^-1,V₁=3.1±1.6 L·kg^-1,AUC=1.7±0.5μg·h^-1·ml^-1。此外,还求得有关肠胃循环的参数,即:重吸收滞后时间T′=0.25±0.24h,重吸收速率常数K_A=3.5±1.4 h^-1,重吸收率R_A=24±7%。     

Influence of sonophoresis and chemical penetration enhancers on percutaneous transport of penbutolol sulfate

The effect of ultrasound and chemical penetration enhancers on transcutaneous flux of penbutolol sulfate across split-thickness porcine skin was investigated. Penbutolol sulfate is a potent, noncardioselective beta-blocker, which is used for the management of hypertension. The drug is one of the most lipid soluble of the β-adrenoceptor antagonists used clinically. It has an n-octanol/pH 7.4 buffer partition coefficient of 179 compared to a value of 22 for propranolol. The amount of penbutolol sulfate transported across the skin is low. In this project, we studied the effect of sonophoresis and chemical penetration enhancers on transdermal delivery of penbutolol sulfate. Low-frequency sonophoresis at a frequency of 20?kHz increased transcutaneous flux of penbutolol sulfate by 3.5-fold (27.37?±?μg?cm^?2?h^?1) compared to passive delivery (7.82?±?1.72?μg?cm^?2?h^?1). We also investigated the effect of 50% ethanol, 1% limonene and 2% isopropyl myristate (IPM) on transcutaneous permeation of penbutolol sulfate. IPM, ethanol and limonene at the concentration of 1%, 50% and 2%, respectively, increased the steady-state flux values of penbutolol sulfate 2.2- (17.07?±?3.24?μg?cm^?2?h^?1), 2.6?- (19.40?±?6.40?μg?cm^?2?h^?1) and 3.4-times (26.38?±?5.01?μg?cm^?2?h^?1) compared to passive delivery (7.76?±?2.9?μg?cm^?2?h^?1). The results demonstrate that although there were slight increases in flux values, ultrasound, ethanol, limonene and IPM did not significantly enhance the transdermal delivery of penbutolol sulfate. Future studies will examine ways of optimizing sonophoretic and chemical enhancer parameters to achieve flux enhancement.     

Population pharmacokinetic analysis of varenicline in adult smokers

AIMS

To characterize the population pharmacokinetics of varenicline and identify factors leading to its exposure variability in adult smokers.

METHODS

Data were pooled from nine clinical studies consisting of 1878 subjects. Models were developed to describe concentration–time profiles across individuals. Covariates were assessed using a full model approach; parameters and bootstrap 95% confidence intervals (CI) were estimated using nonlinear mixed effects modelling.

RESULTS

A two-compartment model with first-order absorption and elimination best described varenicline pharmacokinetics. The final population parameter estimates (95% CI) were: CL/F, 10.4 l h⁻¹ (10.2, 10.6); V₂/F, 337 l (309, 364); V₃/F, 78.1 l (61.9, 98.9); Q/F, 2.08 l h⁻¹ (1.39, 3.79); K_a, 1.69 h⁻¹ (1.27, 2.00); and A_lag, 0.43 h (0.37, 0.46). Random interindividual variances were estimated for K_a[70% coefficient of variation (CV)], CL/F (25% CV), and V₂/F (50% CV) using a block covariance matrix. Fixed effect parameters were precisely estimated [most with % relative standard error < 10 and all with % relative standard error < 25], and a visual predictive check indicated adequate model performance. CL/F decreased from 10.4 l h⁻¹ for a typical subject with normal renal function (CLcr = 100 ml min⁻¹) to 4.4 l h⁻¹ for a typical subject with severe renal impairment (CLcr = 20 ml min⁻¹), which corresponds to a 2.4-fold increase in daily steady-state exposure. Bodyweight was the primary predictor of variability in volume of distribution. After accounting for renal function, there was no apparent effect of age, gender or race on varenicline pharmacokinetics.

CONCLUSIONS

Renal function is the clinically important factor leading to interindividual variability in varenicline exposure. A dose reduction to 1 mg day⁻¹, which is half the recommended dose, is indicated for subjects with severe renal impairment.     

Population pharmacokinetic analysisof lamivudine,stavudine and zidovudine in controlled HIV-infected patients on HAART

Objective This work aimed at building a population pharmacokinetic (PK) model for lamivudine (LMV), stavudine (STV) and zidovudine (ZDV), estimating their inter and intraindividual PK variability and investigating the influence of different covariates. Methods Population PK of LMV, STV and ZDV was separately evaluated from plasma concentrations obtained in 54, 39 and 27 HIV1-infected patients, respectively, enrolled in the COPHAR1-ANRS102 trial. The primary objective of this trial was to study the pharmacokinetics of indinavir (IDV) and nelfinavir (NFV) in treated patients with a sustained virological response. Concentrations of nucleoside analogs (NA) were measured in plasma as a secondary objective. A one-compartment model with first-order elimination was used, with zero-order absorption for LMV and first-order absorption for STV and ZDV. Results Mean parameters [interpatient variability in coefficient of variation (CV%)] of LMV, STV and ZDV were: oral volume of distribution (V/F) 145 l (52%), 24 l (81%) and 248 l (80%), oral clearance (Cl/F) 32 l/h, 16 l/h (74%) and 124 l/h (51%), respectively. For LMV, absorption duration (T _a ) was 1.46 h (64%). For STV and ZDV, k _a was 0.46 h⁻¹ and 2.9 h⁻¹, respectively. We found a systematic effect of combination with NFV vs. IDV. We found that intrapatient variability was greater than interpatient variability (except for STV) and greater than 55% for the three drugs. Conclusion This trial enabled the estimation of the population PK parameters of three NA in patients with a sustained virological response, and the median curves could be used as references for concentration-controlled strategies. We observed, as for the protease inhibitors, a great variability of PK parameters.     

Prediction of clinical pharmacokinetic parameters of linezolid using animal data by allometric scaling: applicability for the development of novel oxazolidinones

1.?Allometric scaling has previously been used as an effective tool for the prediction of human pharmacokinetic data. The pharmacokinetic data for linezolid, a novel oxazolidinone to treat Gram-positive pathogens, in mice, rats and dogs were subjected to simple allometric scaling. Generated allometric equations for parameters such as clearance (CL), volume of distribution (V_ss) and elimination rate constant (K₁₀) were used to predict human pharmacokinetic parameters including elimination half-lives. In addition, the human plasma concentration–time curve was simulated using a one-compartmental model.

2.?Application of simple allometry (Y?=?aW^b) for animal parameters such as CL, V_ss, and K₁₀ showed excellent allometric fit (r?≥?0.98). The allometric equations for CL, V_ss, and K₁₀ were??0.5465W^0.6595,??0.1369W^0.9246, and??0.4117W^–0.3139, respectively. The confidence in predictability of CL and V_ss parameters was particularly high since the allometric exponents of CL and V_ss almost approached the suggested values of 0.75 and 1.00, respectively.

3.?Animal pharmacokinetic parameters generated in the present authors’?laboratories for linezolid were in close agreement with reported literature values. The predicted human values for CL (4.68?l?h^?1), V_ss (37.07 litres), and K₁₀ (0.10?h^?1) were within the range observed for linezolid in the literature (CL?=?4?10.5 l?h^?1; V_ss?=?21???53 litres; K₁₀?=?0.09???0.3?h^?1). The human half-life (t_1/2) predicted using allometry (6.9?h) was similar to reported values in humans of 5?h. In summary, the retrospective analysis for linezolid suggests that allometric scaling can be used as a prospective tool for predicting human pharmacokinetic parameters of novel oxazolidinones.     

马兜铃酸含量的紫外分光光度测定法及药代动力学研究

马兜铃酸系马兜铃属(Aristolochia)植物的有效成分,其药理作用及临床试用已有文献报告。我所植化室从广西马兜铃植物中分离出马兜铃酸,其结构式如图1 本文报道应用薄层层离及紫外分光光度法