厄贝沙坦与氢氯噻嗪联用在大鼠体内剂量优化的定量研究

目的:应用权重配方法及非线性混合效应模型,对厄贝沙坦和氢氯噻嗪在肾性高血压大鼠体内联用的剂量优化进行定量评价。方法:根据权重配方设计,将肾性高血压大鼠分为厄贝沙坦和氢氯噻嗪不同剂量组合的6个用药组,以收缩压和舒张压的变化率作为药效指标。综合建立和应用权重配方模型及非线性混合效应模型分析降压效应,评价两药联用在大鼠体内的降压及交互作用,分析最佳剂量配比,并做确定性实验。对权重配方原法和权重配方群体法的计算结果进行比较。结果:成功建立权重配方模型及其群体模型,联用中组分重要程度为厄贝沙坦大于氢氯噻嗪,厄贝沙坦与氢氯噻嗪存在协同作用,在大鼠体内的最优剂量配比为厄贝沙坦∶氢氯噻嗪=10∶1。权重配方原法和群体法在评价组分重要程度、理论优化组方及剂量优化比例等方面的结论相同,但群体法由于采用个体效应值直接计算,对权重指数等参数的计算更为精确,并提供个体间及个体内变异等信息。结论:综合应用权重配方法及非线性混合效应模型,可定量评价厄贝沙坦和氢氯噻嗪联用在大鼠体内的药物相互作用规律,并提供最佳剂量配比的信息,为临床合理药物联用提供依据。     

厄贝沙坦在健康志愿者体内的药代动力学-药效学结合模型

目的研究厄贝沙坦在健康志愿者体内的药代动力学-药效学结合模型,探讨其临床药效学特征。方法18例健康志愿者厄贝沙坦片口服给药,测定血药浓度,同时测量收缩压(SBP)、舒张压(DBP)及心率(HR)等药效指标。计算厄贝沙坦的药动学参数,并根据sheiner效应室模型理论,计算药效学参数。结果厄贝沙坦的血药浓度时间曲线呈二室模型;厄贝沙坦抑制SBP和DBP的效应滞后于血药浓度,药效与血药浓度之间存在逆时针滞后环,药效和效应室浓度的关系符合SigmoidEmax模型。厄贝沙坦抑制SBP和DBP的药效学参数Emax分别为(14.8±1.5)和(9.8±2.1)mmHg,EC50分别为(0.29±0.11)和(0.18±0.07)mg·L-1,Keo分别为(0.62±0.09)和(0.68±0.07)h-1。结论建立了厄贝沙坦在健康者体内的药代动力学-药效学结合模型,有利于临床合理用药。     

蝙蝠葛苏林碱和蝙蝠葛碱在犬体内的药动学-药效学模型

目的：研究蝙蝠葛苏林碱和蝙蝠葛碱在beagle犬体内的药动学-药效学结合模型,并比较两种药物对其心电、血压和血流动力学的作用。方法：利用反相高效液相色谱法测定其血药浓度,生理记录仪观察药理效应,并计算药动学和药动学-药效学结合模型参数．结果：血药浓度-时间数据符合二房室开放模型．药效与效应室药物浓度之间的关系符合sigmoid-Emax模型．主要药动学和药动学-药效学结合模型参数在两种药物间差异无显著性．结论：蝙蝠葛苏林碱和蝙蝠葛碱在beagle犬体内的处置规律和对心血管系统的抑制作用基本-致。     

厄贝沙坦氢氯噻嗪胶囊在健康人体的生物等效性

目的研究厄贝沙坦氢氯噻嗪胶囊(抗高血压药)在健康人体的生物等效性。方法 22名健康志愿者,随机双交叉单剂量口服厄贝沙坦氢氯噻嗪胶囊(试验制剂)和厄贝沙坦氢氯噻嗪片(参比制剂),剂量为厄贝沙坦300 mg、氢氯噻嗪25 mg。分别于服药后36 h内,多点抽取静脉血,用高效液相色谱法分别测定血浆中厄贝沙坦和氢氯噻嗪的浓度。用DAS程序计算相对生物利用度,并评价2种制剂生物等效性。结果单剂量口服厄贝沙坦氢氯噻嗪胶囊和片剂后的药代动力学参数,厄贝沙坦:Cmax分别为(2.61±0.62)和(2.57±0.46)mg·L-1;AUC0-36分别为(15.14±3.43)和(15.39±3.91)mg·h·L-1;AUC0-∞分别为(16.37±3.42)和(16.80±4.28)mg·h·L-1;相对生物利用度为(100.75±19.42)%。氢氯噻嗪:Cmax分别为(162.51±27.55)和(168.18±25.71)μg·L-1;AUC0-36分别为(1115.41±147.34)和(1144.15±171.62)μg·h·L-1;AUC0-∞分别为(1212.68±160.77)和(1252.75±211.2...     

两种厄贝沙坦氢氯噻嗪片在中国健康受试者体内的生物等效性

目的 研究两种厄贝沙坦氢氯噻嗪片在中国健康受试者体内的生物等效性.方法 空腹试验和餐后试验各入组32例健康受试者,随机、开放、2周期、双交叉单剂量口服厄贝沙坦氢氯噻嗪片(150mg/12.5mg)受试制剂和参比制剂,采用液相色谱串联质谱(LC-MS/MS)法测定给药后不同时间点厄贝沙坦及氢氯噻嗪的血药浓度.采用Phoe...     

苦参碱及氧化苦参碱的药代动力学与药效动力学

以QTc延长率为效应指标,用药代动力学-药效动力学结合模型对苦参碱、氧化苦参碱iv后在免体内的处置和效应动力学作定量分析,两药的血浓时程均符合二房室模型,两药的效应与效应室浓度之间的关系均符合S形E_max模型。两药彼此的药动学和药效学性质均有明显差异,但它们各自的劳动学和药效学性质在所用剂量范围内均为非剂量依赖性。     

华法林和阿司匹林联用在大鼠体内的药代动力学研究(英文)

目的:探讨华法林和阿司匹林联用在大鼠体内非稳态和稳态条件下的药代动力学相互作用的规律,为临床合理药物联用提供依据。方法:将大鼠随机分为3组,即华法林组(0.2mg/kg),阿司匹林组(10mg/kg),华法林(0.2mg/kg)+阿司匹林组(10mg/kg)联用组,每组6只,给大鼠灌胃,连续6d,在第1天和第6天多个时间点取样,分析和比较非稳态和稳态下血药浓度时间曲线和药代动力学参数。结果:华法林药动学用二室模型描述,阿司匹林药动学用一室模型描述。在非稳态和稳态下,阿司匹林单用和联用的血药浓度-时间曲线相似,药代动力学参数之间均无统计学差异;在非稳态下,华法林单用和联用的血药浓度-时间曲线也类似,但在稳态下,联用的血药浓度时间曲线明显高于单用时的曲线,药代动力学计算结果也表明联用时的AUC和Cmax较单用时较大,且有统计意义。结论:当华法林和阿司匹林联用达到稳态时,阿司匹林对华法林的药动学参数有影响,增大了华法林的暴露(AUC和Cmax)。提示两药联用时,很可能增大患者的出血风险,临床上药物联用时应该注意。     

液相色谱-串联质谱法同时测定人血浆中厄贝沙坦和氢氯噻嗪的浓度及药动学

目的建立液相色谱-串联质谱法同时测定血浆中厄贝沙坦和氢氯噻嗪的浓度,并用于人体药动学研究。方法 20名健康受试者单剂量口服试验制剂1片(厄贝沙坦150 mg,氢氯噻嗪12.5 mg)后,在0～36 h内不同时间点分别采集血样,分取血浆,以氯沙坦为内标,经甲醇沉淀蛋白浓缩后流动相溶解,采用CuroSil-PFP色谱柱(Phenomenex 250 mm×4.6 mm,5μm),用含4%冰醋酸的水和含4%冰醋酸的甲醇-乙腈(1∶1,V/V)的流动相梯度洗脱分离,电喷雾离子化串联质谱选择性反应监测(SRM),分别采用正和负离子切换测定厄贝沙坦和氢氯噻嗪在血浆中的浓度。结果厄贝沙坦和氢氯噻嗪血浆样品分别在10～4 000μg.L-1和1～400μg.L-1的浓度范围内质谱响应线性良好。定量下限(LLOQ)分别为10.0μg.L-1和1.0μg.L-1,准确度和精密度良好。受试者单剂量口服厄贝沙坦氢氯噻嗪片1片后,测得氢氯噻嗪的ρmax、tmax、AUC0-36和t1/2分别为(86.96±34.99)μg.L-1、(1.75±0.69)h、(434±143)μg.h.L-1和(7.91±1.31)h;厄贝沙坦的相应参数分别为(1 670±409)μg.L-1、(1.55±0.70)h、(7 396±274)μg.h.L-1和(9.45±5.20)h。结论本方法专属性强、灵敏度高、准确性高,满足厄贝沙坦和氢氯噻嗪药动学研究的要求。     

液质联用法测定人血浆中厄贝沙坦和氢氯噻嗪浓度(英文)

建立了适用于测定人血浆中厄贝沙坦和氢氯噻嗪浓度的液相色谱-质谱(LC-MS)法,并将其应用于厄贝沙坦氢氯噻嗪人体药代动力学研究。人血浆样品采用液-液萃取法提取,内标为对乙酰氨基酚。采用依利特C_(18)柱,以乙腈-水(35:65,v/v)为流动相,选择离子监测负离子模式检测,厄贝沙坦m/z为427.25,氢氯噻嗪m/z为295.95,内标对乙酰氨基酚m/z为150.05。厄贝沙坦和氢氯噻嗪的日内和日间精密度(RSD%)均低于14.5%,准确度(RE%)分别低于1.9%和-2.0%。厄贝沙坦在10-5000ng/mL浓度范围内线性关系良好(r>0.99),氢氯噻嗪在1-200ng/mL浓度范围内线性关系良好(r>0.99)。所建立的方法已成功应用于厄贝沙坦氢氯噻嗪人体药代动力学研究。     

肾康注射液对大鼠体内厄贝沙坦药动学的影响

目的:研究肾康注射液对大鼠体内厄贝沙坦药动学的影响。方法:取18只SD大鼠随机分为对照组(生理盐水)和肾康注射液组(以生药量计为4 g/kg),每组9只,每天ip给药2次,连续给药7 d。末次给药1 h后,两组大鼠均ig厄贝沙坦25 mg/kg,分别于厄贝沙坦给药前及给药后0.25、0.5、1、2、4、8、12、24、32、48、56、72、96 h经眼底静脉丛采血0.3 mL。以联苯双酯为内标,采用高效液相色谱法测定大鼠血浆中厄贝沙坦的血药浓度,利用Phoenix WinNolin~? 6.1药动学软件中非房室模型拟合并计算药动学参数。结果:对照组和肾康注射液组大鼠ig厄贝沙坦后,AUC0-96 h分别为(28.82±10.49)、(35.64±9.99)mg·h/L,c_(max)分别为(0.64±0.15)、(0.76±0.33)mg/L,t_(max)分别为(13.07±16.70)、(10.23±3.97)h,CL_(Z/F)分别为(0.85±0.35)、(0.63±0.21)L/(h·kg),V_(Z/F)分别为(38.24±24.87)、(30.99±9.75)mL/kg,组间比较差异均无统计学意义(P>0.05)。结论:肾康注射液在正常给药剂量下不影响厄贝沙坦在大鼠体内的药动学过程。     

Pharmacokinetic and pharmacodynamic interaction between irbesartan and hydrochlorothiazide in renal hypertensive dogs

Combined irbesartan/hydrochlorothiazide (HCTZ) formulations are often used clinically. Pharmacokinetic-pharmacodynamic (PK/PD) modeling was applied to investigate the pharmacokinetic and pharmacodynamic interaction between irbesartan and HCTZ in renal hypertensive dogs at non-steady-state and steady-state. The renal hypertensive dogs were treated with oral irbesartan alone, or HCTZ alone, or the combination of irbesartan and HCTZ for 8 days. Blood pressure and plasma concentrations were measured and pharmacokinetic-pharmacodynamic parameters were analyzed. Irbesartan showed a two-compartment model pharmacokinetic profile. The concentration-time course of irbesartan was not changed by HCTZ, but irbesartan increased the peak plasma concentration and area under the curve of HCTZ at steady-state. HCTZ had no blood pressure lowering effect at non-steady-state. Irbesartan plus HCTZ had greater blood pressure lowering action than irbesartan alone. HCTZ increased actions of irbesartan. Hysteresis loops were found between effect and plasma concentrations of irbesartan after a single dose. However, hysteresis loops disappeared at steady state with more rapid realization of maximum concentration and effects. The relationship between effects and effect-compartment concentrations of the drugs was represented by a sigmoid Emax model. The results suggest synergistic pharmacodynamic interaction between irbesartan and HCTZ in renal hypertensive dogs and some differences of pharmacokinetic-pharmacodynamic properties between irbesartan and irbesartan/HCTZ combinations at non-steady-state and steady state.     

Pharmacokinetic and pharmacodynamic of irbesartan in renal hypertensive dogs under non-steady-state and steady-state conditions.

The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of irbesartan in renal hypertensive dogs under non-steady-state and steady-state conditions using pharmacokinetic-pharmacodynamic (PK/PD) modeling. Drugs were administered intragastrically to renal hypertensive dogs, plasma drug concentration was determined by HPLC method and Pharmacologic effects, including SBP, DBP, dp/dtmax and LVSP, were measured simultaneously. AT II, Aldosterone (ALD) and Endothelin (ET) were also used as measurement of effect. The PK and PD data were quantitatively analyzed according to the PK/PD model theory. The pharmacokinetic profiles of irbesartan conformed to a two-compartment open model. There was hysteresis loops between effects and plasma concentrations under non-steady-state condition. The relationship between effects and effect compartment concentrations (Ce) could be represented by the Sigmoid-Emax model. The Hysteresis loops disappeared under steady-state condition with more rapidly attainment of maximum concentration and effect. There were certain difference of pharmacokinetic and pharmacodynamic properties between non-steady-state and steady-state condition.     

PK-PD modeling of irbesartan in healthy Chinese adult volunteers under non-steady-state conditions.

The purpose of this study was to construct a pharmacokinetic/pharmacodynamic model (PK-PD model) of irbesartan in healthy Chinese adult volunteers under non-steady-state conditions and provide relevant PK/PD parameters for use in clinical practice. Thirty-six healthy Chinese adult male volunteers received 150 or 300 mg irbesartan orally in tablet form (2 groups; n = 18 per group). Plasma concentrations were determined by HPLC and pharmacological effects, including effects on systolic (SBP) and diastolic blood pressure (DBP) were measured simultaneously. The experimental data were quantitatively analyzed according to the PK-PD model construct. PK/PD parameters were calculated. Blood pressure remained almost unchanged at an irbesartan dose of 150 mg under non-steady-state conditions. After a single dose of 300 mg, the pharmacokinetic profiles of irbesartan conformed to a two-compartment model. There were hysteresis loops between drug effects and plasma concentrations. The relationship between effects and effect compartment concentrations (Ce) could be represented by the sigmoid-Emax model. The Emax values for the inhibitory effects on SBP and DBP of irbesartan were 14.8 +/- 1.5 and 9.8 +/- 2.1 mmHg respectively, the EC50 values were 0.29 +/- 0.11 and 0.18 +/- 0.07 microg x ml(-1), while the K(eo) values were 0.62 +/- 0.09 and 0.68 +/- 0.07 h(-1), respectively. The PK-PD model of irbesartan was developed in healthy Chinese adult male volunteers, and may provide a more rational basis for dosage individualization.     

Pharmacokinetic and pharmacodynamic interaction between tolvaptan, a non-peptide AVP antagonist, and furosemide or hydrochlorothiazide

The pharmacokinetic and pharmacodynamic interactions between tolvaptan and furosemide or hydrochlorothiazide (HCTZ) were determined in a single-center, randomized, open-label, parallel-arm, 3-period crossover study conducted in healthy white (Caucasian) men. A total of 12 subjects were enrolled in the study, with 6 subjects assigned to each of two treatment arms. Subjects in Arm 1 received 30 mg of tolvaptan, 80 mg of furosemide, and 30 mg of tolvaptan + 80 mg of furosemide. Subjects in Arm 2 received 30 mg of tolvaptan, 100 mg of HCTZ, and 30 mg pf tolvaptan + 100 mg of HCTZ. Doses were separated by a 48-hour washout. Blood and urine samples were collected at scheduled timepoints during the 24 hours after administration of study drug for the determination of pharmacokinetic and pharmacodynamic parameters. No clinically significant changes were noted in the pharmacokinetic profiles of tolvaptan and furosemide or tolvaptan and HCTZ when coadministered. Free water clearance, 24-hour urine volume, plasma sodium and argentine vasopressin concentrations, and plasma osmolality were higher, and urine osmolality was lower when tolvaptan was administered either alone or in combination with furosemide or HCTZ, compared with furosemide or HCTZ administered alone. At 24 hours postdose, plasma renin activity was increased after furosemide or HCTZ administered alone or with tolvaptan, but it was unchanged after tolvaptan alone. Tolvaptan did not significantly affect the natriuretic activity of furosemide or HCTZ. Furosemide and HCTZ did not significantly affect the aquaretic activity of tolvaptan. Tolvaptan administered alone or in combination with furosemide or HCTZ was safe and well tolerated at the given doses.     

Accuracy of repeated blood sampling in rats: a new technique applied in pharmacokinetic/pharmacodynamic studies of the interaction between warfarin and co-enzyme Q10

In the past, combined pharmacokinetic/pharmacodynamic (PK/PD) modeling studies of oral anticoagulants in rats have been hampered by the technical problems of blood sampling. In the present study, a semi-micromethod of preparing serial plasma samples for accurate assessment of the prothrombin times (PT) and clotting factor VII activity (CFA) in rats is proposed. The method consists of orbital bleeding, blood sample weighing, gravity calculation and buffer volume adjustment. No significant differences of CFA (percentage normal) were found between citrate-diluted and undiluted plasma. This technique was employed to examine the possibility of PK/PD interaction between warfarin and Co-enzyme Q₁₀ (CoQ₁₀). Rats were given a single oral dose (1.5 mg/kg) of warfarin either alone or on day 4 of an 8-day oral dosing regimen of 10 mg/kg CoQ₁₀ daily. Serial plasma and serum samples, which were subjected to respectively measurements of the anticoagulant effects and concentrations of warfarin and its main metabolites, were obtained over a 96-h period following warfarin administration. All rats survived the whole experiment and maintained a stable condition except for a marked hematocrit decrease. CoQ₁₀ significantly augmented warfarin metabolism but showed little effect on the absorption of warfarin. CoQ₁₀ alone had no apparent effect on either the PT or CFA. The concomitant administration of CoQ₁₀ and warfarin does not significantly affect the anticoagulant effect of warfarin. In conclusion, the proposed serial orbital bleeding technique in rats to prepare an accurate citrate-diluted plasma for PT and CFA measurement is rapid and reliable.     

Population pharmacokinetic and pharmacodynamic modeling of pegvisomant in asian and Western acromegaly patients

Pegvisomant is a growth hormone (GH) receptor antagonist that normalizes insulin-like growth factor I (IGF-I) levels in patients with acromegaly. Although the dose of pegvisomant is determined by the IGF-I level, the pharmacokinetic and pharmacodynamic (PK/PD) model for pegvisomant concentration and IGF-I reduction has not been established. This study was conducted to characterize PK/PD of pegvisomant, and to determine the influence of covariates on the pegvisomant PK/PD. Based on the data from 5 phase III studies in 168 acromegaly patients, models were developed to characterize the PK/PD of pegvisomant. The PD variables were IGF-I serum concentrations. The modeling was performed with a nonlinear mixed-effects approach using NONMEM. After subcutaneous dosing, the PK of pegvisomant was described by a steady state PK model with dose- dependent clearance. Baseline GH and age were significant covariates for the clearance. A sigmoid E(max) model adequately described the relationship between IGF-I and pegvisomant concentrations. Baseline GH was found to be a significant covariate for the baseline effect (E(0)) and IC(50). The PK/PD properties of pegvisomant were not significantly different between Asian and Western patients.     

Do plasma concentrations obtained from early arterial blood sampling improve pharmacokinetic/pharmacodynamic modeling?

In pharmacokinetic/pharmacodynamic (PK/PD) modeling the first blood sample is usually taken 1 to 2 min after drug administration (late sampling). Therefore, investigators have to extrapolate the plasma concentration to Time 0. Extrapolation, however, erroneously assumes instantaneous and complete mixing of drug in the central volume of distribution. We investigated whether plasma concentrations obtained from early arterial blood sampling would improve PK/PD modeling. In 14 pigs, one of five neuromuscular blocking agents (NMBAs) was administered into the right ventricle within 1 sec and arterial sampling was performed every 1.2 sec (1st min). The response of the tibialis muscle was measured mechanomyographically. The influence of inclusion of data from early arterial sampling on PK/PD modeling was determined. Furthermore, the concentrations in the effect compartment at 50% block (EC50) derived from modeling were compared to the measured concentration in plasma during a steady state 50% block. A very high peak in arterial plasma concentration was seen within 20 sec after administration of the NMBA. Extensive modeling revealed that plasma concentrations obtained from early arterial blood sampling improve PK/PD modeling. Independent of the type of modeling, the EC50 and KeO based on data sets that include early arterial blood sampling were, for all five NMBAs, significantly higher and lower respectively, than those based on data sets obtained from late sampling. Early arterial sampling shows that the mixing of the NMBA in the central volume of distribution is incomplete. A parametric PD (sigmoid Emax) model could not describe the time course of effect of the NMBAs adequately.     

Enantioselective pharmacokinetic–pharmacodynamic modelling of carvedilol in a NG‐nitro‐l‐arginine methyl ester rat model of secondary hypertension

Objectives The role of vascular sympatholytic activity of carvedilol in its antihypertensive effect in N^G‐nitro‐l ‐arginine methyl ester (L‐NAME) hypertensive rats was assessed by means of enantioselective pharmacokinetic–pharmacodynamic (PK‐PD) modelling. Methods Male Wistar rats were randomly divided into two groups: control rats received tap water to drink for 2 weeks while L‐NAME rats received L‐NAME solution to drink for 2 weeks. The effects of carvedilol (1 and 5 mg/kg i.v.) on blood pressure, heart rate and blood pressure variability were recorded. Enantioselective carvedilol plasma pharmacokinetics were studied by means of traditional blood sampling. The relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by means of PK‐PD modelling. Vascular sympatholytic activity of carvedilol was assessed by the estimation of drug effects on low frequency blood pressure variability by means of spectral analysis. Key findings A dose‐dependent increase in volume of distribution, as well as a greater volume of distribution and clearance of S‐carvedilol as compared with the R‐enantiomer was found in both experimental groups. Although the PK‐PD properties of the S‐carvedilol chronotropic effect were not altered in L‐NAME rats, hypertensive rats showed greater potency and efficacy to the carvedilol hypotensive response. Greater potency of carvedilol for inhibition of sympathetic vascular activity was found in L‐NAME rats. Conclusions Carvedilol showed enantioselective non‐linear pharmacokinetic properties in both groups. An enhanced hypotensive activity of carvedilol was found in L‐NAME hypertensive rats compared with control rats, which may be explained by the greater potency of carvedilol for sympathetic vascular tone inhibition.     

Linagliptin for the treatment of type 2 diabetes (pharmacokinetic evaluation)

INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) inhibitors offer new options for the management of type 2 diabetes (T2DM). The novel compound linagliptin has important different pharmacokinetic (PK) properties, when compared with previously commercialized DPP-4 inhibitors, which may offer some advantages in clinical practice. Linagliptin has a unique PK/pharmacodynamic (PD) profile and is the first DPP-4 inhibitor with a nonrenal elimination route. Therefore, it can be administered in patients with renal impairment without dose adjustment or monitoring of renal function. The drug has a low potential for drug-drug interactions (DDIs) and no clinically relevant ones were reported so far. AREAS COVERED: An extensive literature search was performed to analyse primarily PK and secondarily PD characteristics of linagliptin in both healthy volunteers and patients with T2DM (treated with linagliptin as monotherapy or combined therapy). Updated information about linagliptin PK either after single administration (large dose range) or after chronic administration (steady state) were also included. A special focus has been put on DDIs and on PK/PD of linagliptin in patients with renal impairment. EXPERT OPINION: Head-to-head comparative studies and/or increased clinical experience with DPP-4 inhibitors will determine the clinical advantage, if any, of one agent over another.