替考拉宁的药动学和药效学特点及给药方案研究进展

摘要：替考拉宁是治疗严重革兰阳性菌感染的首选药物之一。替考拉宁半衰期长,蛋白结合率高,属于时间依赖性药物, 临床疗效与AUC/MIC相关。替考拉宁在不同人群中的药动学参数变异大,应监测替考拉宁谷浓度进行个体化用药方案的调整。 本文通过查阅国内外文献,对替考拉宁在危重症患者、肾功能不全、低蛋白血症、儿童、老年人等特殊人群的药动学、给药方 案进行综述,以期为临床提供参考。     

成年患者替考拉宁群体药动学研究

目的：构建中国成年患者替考拉宁（teicoplanin,TEC）群体药动学（population pharmacokinetics,PPK）模型,探讨TEC药动学参数的影响因素。方法：收集患者的用药信息、血药总浓度、性别、年龄、血清肌酐水平等信息,采用非线性混合效应模型法（nonlinear mixed effect model,NONMEM）建立替考拉宁PPK模型。用图形法、非参数自举法（bootstrap）、正态化预测分布误差法（normalized predictive distribution error,NPDE）进行模型评价。结果：共收集111例成年患者的149个替考拉宁血浆总浓度数据,建立了替考拉宁的一房室PPK模型：CL （L·h^-1）=1.26×（eGFR/82）^0.431,V（L）=83.1,协变量分析显示肌酐清除率（CKD-EPI公式）是影响替考拉宁清除率的重要因素,未发现影响替考拉宁表观分布容积的因素。经验证,最终模型具有良好的拟合优度、稳健率及预测性能。结论：临床可根据患者肌酐清除率（CKD-EPI公式）制定个体化给药方案。     

替考拉宁与万古霉素治疗耐甲氧西林金黄色葡萄球菌肺炎的疗效比较

目的：比较替考拉宁与万古霉素治疗耐甲氧西林金黄色葡萄球菌（ MRSA）肺炎的安全和有效性。方法选取68例MRSA肺炎患者按照随机数字分组法分为两组：观察组34例,采用替考拉宁治疗;对照组34例,采用万古霉素治疗。观察和比较两组的临床疗效、细菌学疗效及不良反应。结果观察组和对照组的临床总有效率分别为82．35％、76．47％,细菌总清除率分别为91．18％、85．29％,两组差异均无统计学意义（均P＞0．05）;观察组出现红斑、皮疹、腹泻各1例,对照组出现肾毒性4例及耳毒性、静脉炎、腹泻各1例,观察组的总不良反应发生率略低于对照组,但差异无统计学意义（P＞0．05）。结论替考拉宁治疗MRSA肺炎的疗效良好、肾损伤较轻,与万古霉素的治疗效果基本相当,值得临床推广和应用。     

耐甲氧西林金黄色葡萄球菌感染的临床治疗

目的观察万古霉素及替考拉宁用于MRSA感染治疗的临床疗效,评价万古霉素及替考拉宁在MRSA感染临床治疗中的应用价值。方法选择60例MRSA感染患者,按照随机原则分为例数相等的两组,其中观察组采用万古霉素治疗,对照组采用替考拉宁治疗,治疗一段时间后,对临床疗效进行比较及统计学分析,观察组间是否存在显著性差异。结果观察组30例患者,有效率93.3%（28/30）;对照组30例患者,有效率66.7%（20/30）,经统计学比较,组间差异具有统计学意义（P〈0.05）。结论万古霉素用于MRSA感染的治疗,具有比替考拉宁更为显著的疗效,值得临床推广应用。     

基于药动学理论脓毒症患者替考拉宁个体化给药分析

目的 探讨临床药师利用药动学理论指导脓毒症患者替考拉宁个体化给药的可行性。方法 临床药师通过参与1例脓毒症抗感染治疗案例,结合监测结果和患者药动学分析,为临床提供药物处置对策和监护建议。结果 临床药师在2次会诊中,结合监测结果对患者进行抗菌药物药动学分析,提出替考拉宁个体化的处置对策和监护计划,保障个体化给药的实施。结论 临床药师对脓毒症患者药动学改变进行全面评估,配合治疗药物监测手段,能够辅助临床医生做好个体化用药工作。     

利奈唑胺与替考拉宁治疗耐甲氧西林金黄色葡萄球菌感染的效果比较

目的:探究利奈唑胺与替考拉宁治疗耐甲氧西林金黄色葡萄球菌(MRSA)感染的疗效和安全性.方法:选取2015年1月～2016年12月我院收治的MRSA感染患者126例作为研究对象,按照治疗方式不同分为利奈唑胺组(n=63)和替考拉宁组(n=63),利奈唑胺组每日静脉滴注利奈唑胺,替考拉宁组每日静脉滴注替考拉宁,比较两组临床疗效、细菌清除率和不良反应发生率.结果:利奈唑胺组总有效率(85.71％)显著高于替考拉宁组(69.84％),差异具有统计学意义(X2=4.5913,P=0.0321);利奈唑胺组细菌清除率(82.54％)显著高于替考拉宁组(65.08％),差异具有统计学意义(X2=4.9677,P=0.0258);利奈唑胺组不良反应发生率(3.17％)显著低于替考拉宁组(12.70％),差异具有统计学意义(X2=3.9103,P=0.0480).结论:利奈唑胺治疗MRSA感染的疗效和安全性均显著优于替考拉宁,值得推广.     

重症感染患者负荷剂量替考拉宁的血药浓度监测

目的:通过监测重症感染患者负荷剂量替考拉宁血药谷浓度,分析药物谷浓度分布情况、达标率、影响因素及临床疗效和安全性,为合理用药提供参考。方法:选取2017年12月至2018年4月解放军总医院重症医学科收治的疑似或确诊多重耐药革兰阳性菌(G~+)感染患者共40例,根据负荷天数不同分为A组(3d,n=22)和B组(4 d,n=18),给予替考拉宁每12 h400 mg,之后以400 mg·d~(-1)维持,分别于首次维持剂量给药前30 min测定替考拉宁血药谷浓度(C_(min));同时测定用药过程中患者肝、肾功能相关指标,记录其不良反应。结果:C_(min)>10 mg·L~(-1)总达标率为65%。A、B2组达标率分别为50.0%和83.3%,差异有统计学意义(P<0.05)。除肌酐清除率(Ccr)外,其余因素对C_(min)无影响。临床好转率95%,用药过程中未出现急性肝、肾损伤。结论:重症感染患者替考拉宁血药浓度随负荷剂量天数增加,血药谷浓度达标率及临床好转率升高,临床用药安全性好。     

大剂量替考拉宁治疗耐甲氧西林金黄色葡萄球菌感染呼吸机相关性肺炎的疗效观察

目的研究大剂量替考拉宁治疗耐甲氧西林金黄色葡萄球菌感染呼吸机相关性肺炎的疗效。方法选取2011年4月至2013年8月接受治疗的86例耐甲氧西林金黄色葡萄球菌感染呼吸机相关性肺炎患者,随机分成大剂量组(n=43例)和小剂量组(n=43例),其中大剂量组患者采用大剂量替考拉宁静脉滴注治疗,小剂量组患者采用小剂量考拉宁静脉滴注治疗,跟踪随访,观察2组患者的疗效、症状改善、细菌清除率、不良反应情况,并记录住院时间。结果大剂量组患者的痊愈率及总有效率明显高于小剂量组(P<0.05);大剂量组患者症状改善用时及住院时长均明显低于小剂量组(P<0.05);大剂量组患者的细菌总清除率明显高于小剂量组患者(P<0.05)。结论大剂量替考拉宁治疗耐甲氧西林金黄色葡萄球菌感染呼吸机相关性肺炎的疗效显著,能明显缩短病程,提供细菌清除率,且不良反应率低,因此具有较高的临床应用价值。     

替考拉宁在不同人群中的药动学及给药方案分析

目的对替考拉宁在不同人群中的药动学及给药方案进行综述,以期为其在国内的临床合理应用提供参考。方法查阅国内外相关文献,归纳替考拉宁在健康志愿者、新生儿和儿童ICU患者、老年人、连续流动时腹膜透析的肾终末期患者、慢性肾功能衰竭患者等人群中的药动学及给药方案。结果与结论替考拉宁具有抗菌优势和低毒性等特点,因而在临床应用上有着广阔的前景,替考拉宁在国内人群中的药动学需要进一步研究。     

利伐沙班在老年非瓣膜性房颤患者中的药动学研究

目的 建立LC-MS/MS测定人血浆中利伐沙班的浓度并进行药动学研究。方法 人血浆样品用乙腈沉淀蛋白后,选用ZORBAX Eclipse XDB C₁₈色谱柱(2.1 mm×100 mm,3.5 mm),以乙腈-10 mmol醋酸铵溶液(含0.1%甲酸)为流动相梯度洗脱,流速为0.30 mL·min^-1,采用电喷雾离子化源,正离子方式,多反应监测扫描方式进行监测,用于定量分析的离子反应分别为m/z 436.2→m/z 145.2(利伐沙班)和m/z 256.1→m/z 165.2(内标苯海拉明)。结果 血浆中利伐沙班的线性范围为5.0~1 000 ng·mL^-1(r=0.995 8),定量下限为5.0 ng·mL^-1;方法回收率为94.1%~106.7%;日内、日间RSD均<15%;提取回收率为84.4%~91.3%,无明显基质效应。结论 该方法快速、灵敏、准确、专属性强、重复性好,适用于人血浆中利伐沙班的血药浓度检测和药动学研究。     

万古霉素与替考拉宁治疗肝移植术后MRSA菌血症疗效与安全性比较

目的：比较万古霉素和替考拉宁治疗重症监护病房肝移植术后耐甲氧西林金黄色葡萄球（MRSA）感染的疗效和安全性。方法：将12例肝移植术后MRSA感染病人随机分为万古霉素治疗组和替考拉宁治疗组,比较两组病人应用抗生素后的治愈率和不良反应。结果：万古霉素与替考拉宁治疗MRSA的治愈率分别为71．4％和60．0％,细菌清除率分别为88．2％和86．7％,不良反应发生率为28．5％和60％,两组间MRSA治愈率有显著性差异（P〈0．05）。结论：万古霉素对重症监护病房肝移植术后MRSA感染的早期治疗效果优于替考拉宁,可以作为此类病人的首选用药。     

Pharmacokinetics of Teicoplanin in An ICU Population of Children and Infants

PURPOSE: Better dosing is needed for antibiotics, including teicoplanin (TEI), to prevent emergence of resistant bacterial strains. Here, we assess the TEI pharmacokinetics (PK) related to a 10 mg/l minimum inhibitory concentration (MIC) target in ICU children (4 to 120 months; n = 20) with gram+ infections. METHODS: Standard administration of TEI was with three 10 mg/kg Q12h, loading infusions, and maintainance with 10 mg/kg or 15 mg/kg Q24h. During maintenance, 9 samples (3/day) were collected per patient and the PK analyzed with Nonlinear Mixed Effects Model (NONMEM). RESULTS: Thirty-five percent of concentrations in older children (> or =2 months) vs. 8% in younger infants (<12 months) were below the target MIC. The global bicompartmental population PK parameters were [mean (interindividual CV%)] CL = 0.23 l/h [72%], V = 3.16 l [58%], k12 = 0.23 h(-1), and k21 = 0.04 h(-1). Two PK subpopulations were identified. The older children had CL = 0.29 [23%] l/h, V = 3.9 l and the younger infants, CL = 0.09 [37%] l/h, V = 1.05 l. Residual error was reduced from 52% to around 30% in the final models. CONCLUSIONS: Older children in the ICU may require relatively higher doses of teicoplanin. However, a study in a larger population is needed.     

Pharmacokinetic/Pharmacodynamic Evaluation of Deflazacort in Comparison to Methylprednisolone and Prednisolone

Purpose. The pharmacokinetics and pharmacodynamics of deflazacort after oral administration (30 mg) to healthy volunteers were determined and compared with those of 20 mg of methylprednisolone and 25 mg of prednisolone. Methods. Methylprednisolone, prednisolone and the active metabolite of deflazacort, 21-desacetyldeflazacort, were measured in plasma using HPLC. For the assessment of pharmacodynamics, differential white blood cell counts were obtained over 24 hours. An integrated pharmacokinetic-pharmacodynamic (PK-PD) model was applied to link corticosteroid concentrations to the effect on lymphocytes and granulocytes. Results. Deflazacort is an inactive prodrug which is converted rapidly to the active metabolite 21-desacetyldeflazacort. Maximum concentrations of 21-desacetyldeflazacort averaged 116 ng/ml and were observed after 1.3 h. The average area under the curve was 280 ng/ml · h, and the terminal half-life was 1.3 h. 21-Desacetyldeflazacort was cleared significantly faster than both methylprednisolone and prednisolone. The PK-PD-model was suitable to describe time course and magnitude of the observed effects. The results were consistent with reported values for glucocorticoid receptor binding affinities for the investigated compounds. Conclusions. Due to the short pharmacokinetic half-life of its active metabolite, pharmacodynamic effects of deflazacort are of shorter duration than those of methylprednisolone and prednisolone. The PK-PD model allows good prediction of pharmacodynamic effects based on pharmacokinetic and receptor binding data.     

利奈唑胺与替考拉宁治疗高龄患者重症MRSA感染的回顾性分析

目的:探讨利奈唑胺与替考拉宁治疗高龄患者院内重症耐甲氧西林金黄色葡萄球菌(MRSA)感染的疗效及安全性。方法:收集高龄男性重症MRSA感染患者临床资料97例,根据使用药物分为利奈唑胺组(42例)和替考拉宁组(55例)。利奈唑胺组给予利奈唑胺600 mg,ivgtt,bid;替考拉宁组给予替考拉宁400 mg,ivgtt,qd,治疗首日剂量加倍。两组疗程均为7~21 d。观察两组患者治疗后临床有效率、细菌清除率、不良反应等。结果:细菌清除率替考拉宁组为52.6%,利奈唑胺组为73.5%,利奈唑胺组细菌清除率显著高于替考拉宁组,差异有统计学意义(χ2=12.57,P=0.034);临床有效率,利奈唑胺组为78.6%,替考拉宁组为58.2%,利奈唑胺组显著高于替考拉宁组,差异有统计学意义(χ2=9.56,P=0.018)。替考拉宁组和利奈唑胺组患者治疗14 d后急性生理及慢性健康评分Ⅱ(APACHEⅡ)评分分别为(14.56±3.04)、(10.29±4.84)分,利奈唑胺组低于替考拉宁组,差异有统计学意义(t=10.97,P=0.014);利奈唑胺组患者不良反应发生率为11.9%,替考拉宁组为20.0%,差异无统计学意义(χ2=1.13,P=0.287)。结论:利奈唑胺治疗高龄患者院内重症MRSA感染疗效显著优于替考拉宁,安全性较好。     

比阿培南在连续性肾替代治疗患者中的药动学研究

目的：建立HPLC法检测血浆和置换液中比阿培南的方法,研究患者在接受连续性肾替代治疗（CRRT）时比阿培南的药代动力学。方法：色谱柱采用ZORBAX Eclipse XDB-C18（4.6mm×150mm,5μm）;以甲醇(A):0.1mmol?L-1醋酸钠溶液(B)（0～6.5min,2%A;6.5～7min, 2%→60%A ;7～15min 60%A）为流动相,检测波长300nm,内标为卡马西平,流速1.0mL?min-1。10名接受CRRT治疗的患者静脉30min匀速滴注比阿培南0.3g。均于给药前及给药后0、5、15、30、45min和1、2、4、6、8h采集滤器前的血液和置换液进行检测。结果：血浆和置换液中比阿培南的浓度在0.20～50.00μg?mL-1范围内线性关系良好;高中低3个浓度的血浆和置换液样品平均回收率分别为(101.05±4.31)% 和(101.09±2.72)%,日内、日间RSD均＜5%,,接受CRRT治疗时比阿培南的药动学以二室模型描述最佳, Cmax为15.37±2.98 mg?L-1、t1/2β为71.36±40.41min、V1为 11.75±3.86L、AUC(0-∞) 为0.64±0.10mg?L-1?min-1。结论：本研究建立的高效液相色谱法灵敏度高、稳定性好、选择性强以及精密度高,比阿培南在接受CRRT治疗时药动学未见明显改变。     

Pharmacokinetics and pharmacodynamics of thiazinamium in asthmatic patients

Summary The pharmacokinetics and pharmacodynamics of thiazinamium (Multergan) were studied after intravenous and intramuscular administration to 7 males with chronic reversible airways obstruction.Disposition after i.v. administration was described by a clearance of 0.54 l·min^–1, central compartment volume of 14.8 l, distribution rate constant 0.092 min^–1, and an elimination rate constant of 0.0044 min^–1. The corresponding estimates after i.m. administration were 0.324 l·min^–1, 34.1 l, 0.035 min^–1, and 0.0018 min^–1. The bronchodilator response (expressed as % predicted FEV1) after i.v. administration was characterized by maximum increase in FEV1 of 33.9%, with an EC₅₀ of 12.8 ng·ml^–1 and an equilibration half-time of 11 min. Corresponding parameter estimates after i.m. administration were 32.2%, 18.8 ng·ml^–1, and 9 min.Anticholinergic activity, measured by the change in heart rate after i.v. administration, showed maximum increase of 76 beats·min^–1, with an EC₅₀ of 176 ng·ml^–1 and an equilibration half-time of 1.3 min. After i.m. administration the corresponding values were 120 beats·min^–1, 250 ng·ml^–1, and 3 min.The optimal plasma concentration of thiazinamium was about 100 ng·ml^–1, which should give a near maximal bronchodilator response (over 80% of predicted normal) and a heart rate of about 100 beats·min^–1.     

Population Pharmacokinetics and Pharmacodynamics of Sotalol in Pediatric Patients with Supraventricular or Ventricular Tachyarrhythmia

Aims: To derive useful pharmacokinetic (PK) and pharmacodynamic (PD) information for guiding the clinical use of sotalol in pediatric patients with supraventricular (SVT) or ventricular tachyarrhythmia (VT).Methods: Two studies were conducted in-patients with SVT or VT in the age range between birth and 12 years old. Both studies used an extemporaneously compounded formulation prepared from sotalol HCl tablets. In the PK study, following a single dose of 30 mg/m² sotalol, extensive blood samples (n=10) were taken. The PK–PD study used a dose escalation design with doses of 10, 30, and 70 mg/m², each administered three times at 8-hr intervals without a washout. Six ECG recordings for determination of QT and RR were obtained prior to the initial dose of sotalol. Four blood samples were collected six ECG's were determined during the third interval at each dose level. Plasma concentrations of sotalol (C) were assayed by LC/MS/MS. The data analysis used NONMEM to obtain the population PK and PD parameter estimates. The individual PK and PD parameters were estimated with empirical Bayes methodology.Results: A total of 611 C from 58 patients, 477 QTc and 499 RR measurements from 23 and 22 patients, respectively, were available for analysis. The PK of sotalol was best described by a linear two-compartment model. Oral clearance (CL/F) and volume of central compartment (Vc/F) were linearly correlated with body surface area (BSA), body weight or age. CL/F was also linearly correlated with creatinine clearance. The best predictor for both CL/F and Vc/F was BSA. The remaining intersubject coefficients of variation (CV's) in CL/F, and Vc/F were 21.6% and 20.3%, respectively. The relationship of QTc to C was adequately described by a linear model. The intersubject CV's in slope (SL) and intercept (E0) were 56.2 and 4.7%, respectively. The relationship of RR to C was also adequately described by a linear model in which the baseline RR and SL were related to age or BSA. The intersubject CV's for SL and E₀ were 86.7 and 14.4%, respectively.Conclusions: BSA is the best predictor for the PK of sotalol. Both QTc and RR effects are linearly related to C. No covariates are found for the QTc–C relation, while the RR–C relation shows age or BSA dependency.     

辛伐他汀在老年高血脂患者中的群体药动学研究

目的：考察老年高血脂患者口服辛伐他汀的药动学模型,为临床制订个体化给药方案提供参考。方法：以30例服用辛伐他汀降血脂的老年高血脂患者为研究对象,于服药前与服药后20、62d3个时间点采血,以高效液相色谱（HPLC）法测定血药浓度,以生化法测定肌酐（Cr）、丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）等实验室检查指标;运用非线性混合效应模型（NONMEM）建立辛伐他汀的药动学模型;考察年龄、体重、肌酐清除率（CLcr）、ALT和AST等对药动学参数的影响,并以Bootstrap法进行模型验证。结果：本研究建立了口服辛伐他汀一级吸收和消除的一房室群体药动学模型;年龄、体重、CLcr等因素加入模型之后,基本模型并未改变（P〉0.05）。辛伐他汀表观清除率和表观分布容积的群体典型值分别为1020L·h-1和2350L。结论：本研究建立了老年高血脂患者口服辛伐他汀的群体药动学模型,为临床合理使用该药提供了依据。