治疗性蛋白药物的药动学和药效学评价

治疗性蛋白药物是一类用于治疗的高分子物质(>1kDa)可分为多肽和基因工程药物、单克隆抗体和基因工程抗体、重组疫苗等。与小分子药物相比,其具有高活性、特异性强、低毒性、生物功能明确、有利于临床应用的特点。由于其成本低、成功率高、安全可靠,故已成为医药产品中的重要组成部分。同时,由于该类药物为外源性蛋白,具有稳定性不高、分子量大以及物理化学性质与小分子药物不同等特点,其药动学和药效学研究面临许多困难。本文从药动学和药效学两个方面,综述治疗性蛋白药物的影响因素和研究方法。1治疗性蛋白药物的药动学1.1吸收由于蛋白质…     

抗真菌药物的药动学和药效学研究进展

目的:介绍临床常用抗真菌药物的药动学和药效学研究进展,旨在为临床合理用药提供相关依据。方法:查阅国内、外相关文献,进行系统的阅读复习,并进行综合分析。结果:真菌感染发病复杂,诊断困难,预后较差,但是抗真菌药物研发的不断进步,为临床医生用药提供了更多选择,真菌感染的治疗和预后将逐步得到改善。结论:临床常用抗真菌药物的药动学和药效学研究,对于临床合理用药具有重要的指导意义。     

依据药动学和药效学参数合理使用抗菌药物

抗菌药物的药理学研究内容主要包括药代动力学(PK)与药效学(PD)。随着研究的不断深入,人们发现抗菌药物PK/PD参数与药物的临床疗效密切相关。依据抗菌药物对细菌作用的方式和PK/PD特性,将抗菌药物分为浓度依赖型抗菌药     

光学活性药物的药动学和药效学差异

综述近几年手性药物的研究状况和临床应用结果 ,探讨不同光学活性药动学及药效学特征 ,阐明其药理活性和不良反应实质。近年来的文献报道和临床研究表明有些手性药物在临床上的应用是有益的 ,有些会造成严重后果 ,对手性药物的深入研究将会为临床合理应用手性药物带来积极的意义     

抗菌药物的药动学和药效学参数对临床用药的意义

目的探讨抗菌药物药动学／药效学（PK／PD）参数的应用及其对临床用药的指导意义。方法120例择期行I、Ⅱ类手术患者随机分为研究A组、研究B组、对照A组和对照B组,每组30例,研究A组和对照A组术后给予氨基糖苷类抗菌药预防感染,但用法与用量不同,研究B组与对照B组术后给予克林霉索类抗菌药预防感染,但切口细菌学检测时间不同。分别比较研究A组与对照A组患者切口感染及愈合时间,比较研究B组与对照B组患者切口细菌检测阳性情况。结果研究A组患者临床感染率明显低于对照A组（P〈0．05）,切口平均愈合时间明显短于对照A组（P〈0．01）。研究B组未检测出阳性病例,对照B组检测有5例患者切口可测得细菌阳性,研究B组患者阳性检测出率明显低于对照B组（P〈0．05）。结论PK／PD对于临床高效和准确应用抗菌药具有积极的指导意义,对浓度依赖性抗菌药应一次给足剂量,对时间依赖性抗菌药应在给予适当剂量的基础上耐心观察效果,避免因短时间内未见效就立刻更换用药。     

家兔体内呋喃苯胺酸的药动学和药效学结合模型

用药动学-药效学结合模型对呋喃苯胺酸在家兔体内的处置和效应动力学作定量分析。呋喃苯胺酸的k_(eo),S,E_(max),EC_(50)分别为0.131±0.029min~(-1),2.21±0.61,6.5±0.6ml/min,3.49±0.77μg/ml。结果表明血浆与作用部位属于不同的房室,两者之间存在着一个平衡过程。     

喹诺酮类抗菌药物的药动学和药效学研究进展

喹诺酮类是目前临床普遍使用的一类抗菌药物.现从体外实验、动物实验和人体试验等方面对其药动学/药效学(PK/PD)研究进行了综述,并对PK/PD与细菌耐药及其在临床上的应用进行了简介.     

Pharmacokinetic/pharmacodynamic evaluation of inhalation drugs: application to targeted pulmonary delivery systems

Inhaled therapy with either glucocorticoids and/or β₂-adrenergic drugs remains the mainstay of asthma treatment. In the last few years, a number of new products have been introduced into the market with the goal of improving efficacy and safety. This review article summarises the pharmacokinetic and pharmacodynamic properties of inhaled drugs for topical delivery necessary to achieve this goal. Pharmacokinetic properties include a high pulmonary deposition, low oral bioavailability, optimised pulmonary residence time and a very high systemic clearance. Optimisation of pharmacodynamic properties, such as receptor selectivity, may also yield drugs with improved pulmonary selectivity. As existing drugs also provide high efficacy and safety profiles, future developments will represent only slight improvements and quantum leap improvements are unlikely to occur.     

Pharmacokinetic and pharmacodynamic interactions of aspirin with warfarin in beagle dogs

1.?Warfarin and aspirin are widely used in a wide spectrum of thromboembolic and atherothrombotic diseases. Despite the potential efficacy of warfarin–aspirin therapy, the safety and side effect of combined therapy remains unclear.

2.?The aim of this study was to investigate the pharmacokinetic and pharmacodynamic interactions between warfarin and aspirin in beagles after single and multiple doses.

3.?Coadministration of aspirin had no significant effects on the area under the plasma concentration time curve (AUC_0–t) and maximum plasma concentration (C_max) of R- and S-warfarin after a single dose of warfarin, but significantly increase the AUC_0–t and C_max and dramatically decrease the clearance (CL) of R- and S-warfarin after multiple dose of warfarin. Accordingly, there was a slight increase in the AUEC_0–t and E_max of activated partial thromboplastin time (aPTT), prothrombin time (PT) and international normalized ratio (INR) after multiple dose of warfarin.

4.?Coadministration of warfarin had no markedly effects on the AUC_0–t and C_max of aspirin and its metabolite salicylic acid after single or multiple dose of aspirin. Meanwhile, the AUEC_0–t and E_max of inhibition of platelet aggregation (IPA) were not significantly affected by warfarin.

5.?Our animal study indicated that coadministration of aspirin with warfarin can cause significant pharmacokinetic and pharmacodynamic drug–drug interactions in beagles. However, more studies are urgently needed to assess related information of warfarin–aspirin drug interactions in healthy volunteers or patients.     

三七总皂苷鼻用凝胶喷雾剂的药动学与药效学研究

目的研究自制三七总皂苷鼻用凝胶喷雾剂的生理适应性、家兔给药后体内的药动学过程,及其对心血管疾病的保护作用。方法选用扫描电镜法,考察喷雾剂的鼻纤毛毒性;HPLC法测定三七总皂苷鼻用凝胶喷雾剂家兔鼻腔给药后血样中人参皂苷Rb1、Rg1的浓度,考察药物在体内的动力学过程,并计算药动学参数;建立大鼠急性缺血性心肌梗死模型,考察三七总皂苷鼻用凝胶喷雾剂对心脑血管疾病的保护作用。结果三七总皂苷鼻用凝胶喷雾剂给药后,Rb1、Rg1在家兔体内的过程符合二室模型,其绝对生物利用度比三七总皂苷滴鼻液高,分别为（42．31±7．54）％和（81．06±32．71）％;可大幅减少大鼠左冠状动脉闭塞所致的心肌梗死面积,且呈剂量依赖性,剂量越高,保护作用越强;该喷雾剂基本无明显鼻纤毛毒性。结论药动学、药效学及鼻纤毛毒性试验结果证明,三七总皂苷鼻腔给药制剂具有很好的开发前景。     

Pharmacokinetic pharmacodynamic evaluation of the combined administration of alprazolam and fluoxetine

The pharmacokinetic and pharmacodynamic effects of concomitant administration of alprazolam and fluoxetine were studied in this double-blind parallel study in 80 healthy, male volunteers. Subjects were randomly assigned to one of four treatment groups. Drug treatments consisted of 4-day regimens of 1 mg alprazolam four times daily, 60 mg fluoxetine every morning, 1 mg alprazolam four times daily and 60 mg fluoxetine every morning, and placebo four times daily. Psychomotor performance, mood status, and degree of sedation were evaluated at designated times. Combined administration of alprazolam and fluoxetine resulted in an approximate 30% increase in plasma alprazolam concentrations relative to plasma concentrations following the administration of alprazolam alone. There were no significant differences in fluoxetine or norfluoxetine plasma concentrations between the alprazolam/fluoxetine and fluoxetine treatments. Psychomotor decrements increased when fluoxetine was administered with alprazolam relative to alprazolam administration alone. Psychomotor performance of the fluoxetine treatment group was not significantly different from that of the placebo group. No significant changes were observed in mood status, and sedation was minimal in all treatment groups. As when any two psychoactive drugs are administered together, increased patient monitoring and patient education is recommended when alprazolam and fluoxetine are prescribed concurrently.     

Pharmacokinetic and pharmacodynamic modelling with pancuronium

Summary The pharmacokinetics and pharmacodynamics of pancuronium were studied following intravenous infusion in eleven patients undergoing surgical anaesthesia. Measurement of the plasma concentrations (C_p) of the neuromuscular blocking agent (NMBA) and the concomitant intensities of paralysis allowed their simultaneous modelling. The pharmacokinetic parameters derived for pancuronium were in the range of previously reported values, except that the mean total systemic plasma clearance (0.79±0.28 ml·min^–1·kg^–1) was reduced and the mean terminal phase half-life (169 min) was longer in these patients. Plasma concentration and % paralysis data were successfully fitted to a previously proposed pharmacodynamic model. This model assumes a separate effect compartment which exchanges drug directly with the central kinetic compartment (integrated effect model). The steady-state C_p necessary to produce 50% paralysis (EC_pss(50)) was estimated to be 0.21±0.08 µg·ml^–1 (mechanical response) and 0.18±0.05 µg·ml^–1 (EMG response). An analysis using the Hill equation of the C_p-response relationship, during and after the constantrate infusion of pancuronium bromide, resulted in effective plasma concentrations for 50% paralysis (EC_p50) of 0.35±0.06 µg·ml^–1 and 0.20±0.09 µg·ml^–1, respectively, for mechanical twitch response. The corresponding values for EMG response were 0.32±0.06 µg·ml^–1 and 0.17±0.06 µg·ml^–1. Using this latter approach, the EC_p50 estimated during onset of paralysis was significantly higher than that estimated during offset of paralysis (p<0.05); no such difference was apparent between this latter parameter and the EC_pss(50) of the integrated effect model (p>0.05). No significant differences were observed between any of the pharmacodynamic parameter estimates generated from the data obtained from the two methods of assessment of neuromuscular function (mechanical vs. EMG response) (p>0.05).     

Pharmacokinetic and pharmacodynamic study of the combination of furosemide retard and triamterene

Summary The pharmacodynamics and pharmacokinetics of the combination of furosemide retard (30 mg)/triamterene (50 mg) were compared with furosemide (30 mg) in 18 healthy male volunteers aged 39.3±6.3 years. After the administration of furosemide the onset of its effect was very rapid, reaching a maximum between 1.5 to 3 h, and followed by rebound after 9 to 10.5 h. In contrast the combination furosemide retard/triamterene showed a protracted course with a duration of effect up to 12 h. The general effect over 12 h of the two preparations was equivalent with respect to the excretion of urine, sodium, chloride and calcium, but the combination caused significantly less excretion of potassium (p0.05) than furosemide. After a lag-phase of 33.9±5.4 min the maximum plasma concentration of furosemide was reached after 3.47±0.66 h, and the elimination half-life was approximately 2 h. After a lag-phase of 33.0±17.8 min the maximum plasma concentration of the main metabolite of triamterene, the OH-TA sulphuric acid ester, was reached after 1.7±0.59 h, and its elimination half-life amounted to 1.25±0.37 h. Because of the sustained release of furosemide from the retard-formulation, its principal pharmacokinetic parameters were better adapted to those of triamterene. The consequences were not only a protracted effect but also an improved electrolyte profile, especially with regard to reduced loss of potassium. In the case of renal insufficiency, however, the potassium level in serum might be increased to an undesirable extent.     

Pharmacokinetic and pharmacodynamic drug evaluation of tofogliflozin for the treatment of type 2 diabetes

Introduction: Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are a new class of drugs that are increasingly used for the management of type 2 diabetes mellitus (T2DM). Among these, tofogliflozin has recently received marketing approval in Japan.

Areas covered: In this review, the authors summarize the pharmacokinetic and pharmacodynamic profile of tofogliflozin for the treatment of T2DM, and provide a rationale for its use in such patients.

Expert opinion: Despite the very promising characteristics of tofogliflozin in improvement of glycemic and metabolic parameters, a number of issues await consideration. One important question relates to the manner in which tofogliflozin mediates metabolic changes. Additionally, safety issues, namely hypoglycemia, diabetic ketoacidosis, pollakiuria and polyuria, urinary and genital tract infections, and potential other adverse events, need to be better monitored by pharmacovigilance programs. Ultimately, although tofogliflozin seems a promising agent that physicians are likely to embrace with excitement in the T2DM therapeutic area, longer duration trials are expected to verify this speculation and to increase our experience.     

Pharmacokinetic and pharmacodynamic comparison of hydrofluoroalkane and chlorofluorocarbon formulations of budesonide

AIMS

A hydrofluoroalkane formulation of budesonide pressurized metered-dose inhaler has been developed to replace the existing chlorofluorocarbon one. The aim of this study was to evaluate the pharmacokinetic and pharmacodynamic characteristics of both formulations.

METHODS

Systemic bioavailability and bioactivity of both hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler formulations at 800 µg twice daily was determined during a randomized crossover systemic pharmacokinetic/pharmacodynamic study at steady state in healthy volunteers. Measurements included the following: plasma cortisol AUC_24h[area under the concentration-time curve (0–24 h)], budesonide AUC_0–12h and C_max. Clinical efficacy was determined during a randomized crossover pharmacodynamic study in asthmatic patients receiving 200 µg followed by 800 µg budesonide via chlorofluorocarbon or hydrofluoroalkane pressurized metered-dose inhaler each for 4 weeks. Methacholine PC₂₀ (primary outcome), exhaled nitric oxide, spirometry, peak expiratory flow and symptoms were evaluated.

RESULTS

In the pharmacokinetic study, there were no differences in cortisol, AUC_0–12h[area under the concentration-time curve (0–12 h)], T_max (time to maximum concentration) or C_max (peak serum concentration) between the hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler. The ratio of budesonide hydrofluoroalkane vs. chlorofluorocarbon pressurized metered-dose inhaler for cortisol AUC_24h was 1.02 (95% confidence interval 0.93–1.11) and budesonide AUC_0–12h was 1.03 (90% confidence interval 0.9–1.18). In the asthma pharmacodynamic study, there was a significant dose response (P < 0.0001) for methacholine PC₂₀ (provocative concentration of methacholine needed to produce a 20% fall in FEV₁) with a relative potency ratio of 1.10 (95% confidence interval 0.49–2.66), and no difference at either dose. No significant differences between formulations were seen with the secondary outcome variables.

CONCLUSIONS

Hydrofluoroalkane and chlorofluorocarbon formulations of budesonide were therapeutically equivalent in terms of relative lung bioavailability, airway efficacy and systemic effects.     

Pharmacokinetic and pharmacodynamic characterization of gliclazide in healthy volunteers

Pharmacokinetic and pharmacodynamic properties of gliclazide were studied after an oral administration of gliclazide tablets in healthy volunteers. After an overnight fasting, gliclazide tablet was orally administered to 11 volunteers. Additional 10 volunteers were used as a control group (i.e., no gliclazide administration). Blood samples were collected, and the concentration determined for gliclazide and glucose up to 24 after the administration. Standard pharmacokinetic analysis was carried out for gliclazide. Pharmacodynamic activity of the drug was expressed by increase of glucose concentration (deltaPG), by area under the increase of glucose concentration-time curve (AUC(deltaPG)) or by the difference in increase of glucose concentration (D(deltaPG)) at each time between groups with and without gliclazide administration. Pharmacokinetic analysis revealed that Cmax, Tmax, CL/F (apparent clearance), V/F (apparent volume of distribution) and half-life of gliclazide were 4.69+/-1.38 mg/L, 3.45+/-1.11 h, 1.26+/-0.35 L/h, 17.78+/-5.27 L, and 9.99+/-2.15 h, respectively. When compared with the no drug administration group, gliclazide decreased significantly the AUC(deltaPG) s at 1, 1.5, 2, 2.5, 3 and 4 h (p<0.05). The deltaPGs were positively correlated with AUC(gliclazide) at 1 and 1.5 h (p<0.05), and the correlation coefficient was maximum at 1 h (r = 0.642) and gradually decreased at 4 h after the administration. The AUC(deltaPG)s were positively correlated with AUC(gliclazide) at 1, 2, 3 and 4 h (p<0.05), and the maximum correlation coefficient was obtained at 2 h (r=0.642) after the administration. The D(deltaPG) reached the maximum at 1 h, remained constant from 1 h to 3 h, and decreased afterwards. Therefore, these observations indicated that maximum hypoglycemic effect of gliclazide was reached at approximately at 1.5 h after the administration and the effect decreased, probably because of the homeostasis mechanism, in health volunteers.     

Pharmacokinetic drug evaluation of velpatasvir plus sofosbuvir for the treatment of hepatitis C virus infection

Introduction: The fixed-dose combination therapy of sofosbuvir (SOF) plus velpatasvir (VEL) is the first pangenotypic, direct-acting antiviral (DAA), single-treatment regimen (STR) for the treatment of hepatitis C virus (HCV) infection to be commercialized. It is approved for the treatment of HCV genotypes 1, 2, 3, 4, 5, and 6. Following approval in 2016, new pharmacokinetic and pharmacodynamic data were reported, which led to important clinical applications.

Areas covered: This review provides a summary of the pharmacokinetics, pharmacodynamics, efficacy and safety of SOF/VEL therapy for treatment of HCV infection. The topics covered include data regarding the drug’s absorption, distribution, metabolism, excretion and antiviral activity strategies, such as clinical dose selection and treatment duration.

Expert opinion: This novel combination therapy containing 400 mg of SOF plus 100 mg of VEL, taken orally, once daily, with or without food, has an excellent pharmacokinetic and pharmacodynamic profile. SOF/VEL achieved very high rates of sustained virological response in treatment-naive and treatment-experienced patients with chronic HCV genotype 1–6 infection, including those with compensated cirrhosis or HIV-1 co-infection.