肾移植患者吗替麦考酚酯血药浓度监 测简

目的：探讨对吗替麦考酚酯进行治疗药物监测的临床必要性.方法：采用HPLC方法测定血浆中麦考酚酸的谷浓度和峰浓度,对2012 年10 – 12 月期间83 例肾移植患者血浆麦考酚酸浓度进行分析.结果：患者血浆麦考酚酸谷浓度在0.34 ～ 3.99 μg·mL-1范围内的共46例次,血浆麦考酚酸峰浓度在0.91～12.78 μg·mL-1范围内的有37例次.在固定给药剂量下,麦考酚酸血药浓度的个体差异较大.结论：对吗替麦考酚酯进行治疗药物监测具有重要的临床价值.     

Mycophenolic acid trough level monitoring in solid organ transplant recipients treated with mycophenolate mofetil: association with clinical outcome

ABSTRACT

Background: Mycophenolate mofetil (MMF) is widely and successfully used in immunosuppressive regimens for the prophylaxis of organ rejection following transplantation. Conventionally, it is administered at a fixed dose without serial measurements of plasma concentrations of mycophenolic acid (MPA), the active metabolite. Recently, there has been an increased interest in therapeutic drug monitoring (TDM) of MMF therapy to optimize the benefit/risk index of the drug. Predose trough samples of MPA are considered most convenient and economic, thereby allowing an increased use of TDM in the transplant setting. However, the added value of TDM for MMF therapy is still under debate.

Objective: This paper reviews (based on a systematic PubMed and EMBASE search, 1995–June 2006) the current evidence of the usefulness and clinical relevance of MPA trough level monitoring during MMF therapy in solid organ transplantation.

Findings and conclusions: Based on data available in the public domain, the contribution of MPA trough level monitoring during MMF therapy in solid organ transplant recipients remains unproven. Available studies have limitations and report conflicting results. There is a lack of prospective randomized trials, particularly in pediatric renal transplant recipients and in cardiac and liver transplantation. While there is a suggestion that there may be a relationship between efficacy and MPA trough levels, the majority of studies showed no correlation between MPA plasma concentrations and adverse effects. Based on current evidence, the adherence to presently recommended target ranges for MPA troughs in solid organ transplantation cannot assure an improved clinical outcome with MMF therapy. Whether MPA trough level monitoring leads to improved efficacy and less toxicity is currently subject to a large randomized trial; final results are eagerly awaited.     

Therapeutic drug monitoring in a developing country: an overview

Therapeutic Drug Monitoring (TDM) was introduced in India in the mid and late 1980s and the last 10 years have seen it grow, together with the growth of separate Clinical Pharmacology departments. The TDM service in the country is broadly of two types: in large teaching hospitals where the service is available through departments of Clinical Pharmacology, and in the private sector, where drug estimations are done by clinical biochemistry departments with minimal interpretation. This article is based on literature review and our own experiences over a 10 year period in a department of Clinical Pharmacology. It focuses on the evolution of TDM, its problems such as lack of funding, special aspects such as the impact of ethnic diff;erences, nutritional defi;ciencies, quality of medicines and availability of generic products; its utility as a research tool and its future.     

Therapeutic drug monitoring in a developing country: an overview

Therapeutic Drug Monitoring (TDM) was introduced in India in the mid and late 1980s and the last 10 years have seen it grow, together with the growth of separate Clinical Pharmacology departments. The TDM service in the country is broadly of two types: in large teaching hospitals where the service is available through departments of Clinical Pharmacology, and in the private sector, where drug estimations are done by clinical biochemistry departments with minimal interpretation. This article is based on literature review and our own experiences over a 10 year period in a department of Clinical Pharmacology. It focuses on the evolution of TDM, its problems such as lack of funding, special aspects such as the impact of ethnic differences, nutritional deficiencies, quality of medicines and availability of generic products; its utility as a research tool and its future.     

免疫抑制剂治疗药物监测在器官移植领域的应用进展

排斥反应是影响异体器官移植术后移植器官长期存活的独立危险因素，免疫抑制剂的应用可预防排斥反应发生，极大地提高了患者移植物的存活率，但临床上在使用免疫抑制剂过程中，需要对治疗药物进行浓度监测。目前常用的检测方法有免疫分析法及色谱法，其中液相色谱串联质谱法因具有专属性强、准确度高、分析快速、灵敏度高等优点，大多数临床实验室以该测定方法作为治疗药物监测的金标准。基于临床常用免疫抑制剂的药理及药动学特性，将免疫抑制剂的检测方法分为全血型免疫抑制剂的检测与血浆型免疫抑制剂的检测，并分别对两类药物的血药浓度监测方法进行综述，旨在为免疫抑制剂在器官移植领域的临床安全合理用药提供更直接的指导依据。     

Therapeutic drug monitoring: antiarrhythmic drugs

Antiarrhythmic agents are traditionally classified according to Vaughan Williams into four classes of action. Class I antiarrhythmic agents include most of the drugs traditionally thought of as antiarrhythmics, and have as a common action, blockade of the fast-inward sodium channel on myocardium. These agents have a very significant toxicity, and while they are being used less, therapeutic drug monitoring (TDM) does significantly increase the safety with which they can be administered. Class II agents are antisympathetic drugs, particularly the b-adrenoceptor blockers. These are generally safe agents which do not normally require TDM. Class III antiarrhythmic agents include sotalol and amiodarone. TDM can be useful in the case of amiodarone to monitor compliance and toxicity but is generally of little value for sotalol. Class IV antiarrhythmic drugs are the calcium channel blockers verapamil and diltiazem. These are normally monitored by haemodynamic effects, rather than using TDM. Other agents which do not fall neatly into the Vaughan Williams classification include digoxin and perhexiline. TDM is very useful for monitoring the administration (and particularly the safety) of both of these agents.     

Therapeutic drug monitoring: antiarrhythmic drugs

Antiarrhythmic agents are traditionally classified according to Vaughan Williams into four classes of action. Class I antiarrhythmic agents include most of the drugs traditionally thought of as antiarrhythmics, and have as a common action, blockade of the fast-inward sodium channel on myocardium. These agents have a very significant toxicity, and while they are being used less, therapeutic drug monitoring (TDM) does significantly increase the safety with which they can be administered. Class II agents are antisympathetic drugs, particularly the β-adrenoceptor blockers. These are generally safe agents which do not normally require TDM. Class III antiarrhythmic agents include sotalol and amiodarone. TDM can be useful in the case of amiodarone to monitor compliance and toxicity but is generally of little value for sotalol. Class IV antiarrhythmic drugs are the calcium channel blockers verapamil and diltiazem. These are normally monitored by haemodynamic effects, rather than using TDM. Other agents which do not fall neatly into the Vaughan Williams classification include digoxin and perhexiline. TDM is very useful for monitoring the administration (and particularly the safety) of both of these agents.     

Therapeutic drug monitoring – antiepileptic drugs

Aims  To provide a brief critical review of the basis and contemporary practice of monitoring the concentrations of antiepileptic drugs in biological fluids.
Methods  The review is based on literature data and observations from clinical practice.
Results  As experience has accumulated, monitoring of antiepileptic drug concentrations has come to be applied mainly to certain of the drugs when present in whole plasma. For these drugs there is a reasonably established relationship between drug concentrations and biological effects, but attention still needs to be paid to issues such as the timing of the measurements in relation to drug intake, the presence or absence of steady-state conditions, the presence in plasma of active metabolites and possible nonlinear pharmacokinetics of particular agents, e.g. phenytoin.
Conclusions  Plasma antiepileptic drug concentration monitoring is coming to be used in a more thoughtful and critical manner. Lack of adequate knowledge of matters such as the relationship between the plasma concentrations and antiepileptic and toxic effects of the drugs, not only the newer, but also the longer established ones, in particular clinical situations, remains more important than deficiencies in analytical methodology in limiting the clinical usefulness of antiepileptic drug concentration monitoring.     

肝移植术后环孢素治疗药物监测

目的:研究肝移植受者环孢素A临床药动学特点,优化环孢素A治疗药物监测方案。方法:采用荧光偏振免疫法测定环孢素A血药浓度,计算临床药动学参数。建立AUC0-12h与浓度变量回归模型。对C0、C2常规监测数据进行分析。结果:环孢素代谢呈二房室开放模型。C0 C2与AUC0-12h相关较为强烈,C2与AUC0-4h和AUC0-12h的相关性高于C0。在估算AUC0→12h的回归模型中,C0 C2最好,SE和R-sq分别为501.0和94.7,其后是C6,C2,C9,C4和C0。结论:环孢素A临床药动学个体差异大。C0 C2两点监测是环孢素A最好的监测方法,可客观评价环孢素A体内药物暴露(AUC0-12h),减少急性排斥和药物中毒发生。C2/C0可以作为评价移植肝功能恢复的灵敏指标。     

Safety of mTOR inhibitors in adult solid organ transplantation

ABSTRACT

Introduction: Mammalian target of rapamycin (mTOR) inhibitors (sirolimus and everolimus) are a class of immunosuppressive drugs approved for solid organ transplantation (SOT). By inhibiting the ubiquitous mTOR pathway, they present a peculiar safety profile. The increased incidence of serious adverse events in early studies halted the enthusiasm as a kidney sparing alternative to calcineurin inhibitors (CNI).

Areas covered: Herein we review mTOR inhibitors safety profile for adult organ transplantation, ranging from acute side effects, such as lymphoceles, delayed wound healing, or cytopenias, to long-term ones which increase morbidity and mortality, such as cancer risk and metabolic profile. Infection, proteinuria, and cutaneous safety profiles are also addressed.

Expert opinion: In the authors’ opinion, mTOR inhibitors are a safe alternative to standard immunosuppression therapy with CNI and mycophenolate/azathioprine. Mild adverse events can be easily managed with an increased awareness and close monitoring of trough levels. Most serious side effects are dose- and organ-dependent. In kidney and heart transplantation mTOR inhibitors may be safely used as either low-dose de novo or through early-conversion. In the liver, conversion 4 weeks post-transplantation may reduce long-term chronic kidney disease secondary to calcineurin nephrotoxicity, without increasing hepatic artery/portal vein thrombosis.     

器官移植患者的霉酚酸酯治疗药物监测

麦考酚酸酯（霉酚酸酯,mycophenlate mofetil,MMF）是麦考酚酸（霉酚酸,mycophenolic acid,MPA）的一种酯类衍生物。MMF无生物活性,口服后迅速水解为具活性的MPA。MMF是近年来发现的一种新型免疫抑制剂,临床上主要用于预防和治疗器官移植排斥反应。     

肾移植术后受者环孢素的血药浓度监测

目的 观察环孢素血药浓度与肾移植效果间关系。方法 对９７例接受同种异体肾脏移植术受者术后８周内２０６例次环孢素血药浓度监测结果进行回顾性分析，按照受者术后的临床表现、生化指标将其分为术后正常组、急性排斥组、急性毒性组，采用荧光偏振免疫测定法，以单克隆抗体试剂测定环孢素血药浓度。结果 术后正常组６２例移植肾功能良好，环孢素的给药剂量为５２±１．９ ｍｇ／ｋｇ·ｄ，１７１例次环孢素血药浓度的平均值为３０９．８５±１３１．６９μｇ／Ｌ；术后急性排斥组 ２６例，距发生排斥反应最近一次的环孢素血药浓度平均为１６５．８０±１２３．１３μｇ／Ｌ，环孢素的给药剂量为 ４．８±１．６ｍｇ／ｋｇ·ｄ；术后急性毒性组９例，距发生毒性反应最近一次的环孢素血药浓度平均为５５６．５１±１０２．５０μｇ／Ｌ，环孢素的给药剂量为６．２±１．０ｍｇ／ｋｇ·ｄ。三组之间环孢素的给药剂量无显著性差异（Ｐ＞０．０５），但环孢素血药浓度却相差很大，两两之间有显著性差异（正常组与排斥组 Ｐ＜ ０．０５；正常组与毒性组Ｐ＜ ０．０５；排斥组与毒性组Ｐ＜ ０．０１）。结论 环孢素浓度较低时，出现排斥反应的可能性较大；而环孢素浓度较高时，发生毒性反应的机会较多。     

Therapeutic monitoring of cyclosporin — an update

Summary The success of organ transplantation is closely related to clinical use of the immunosuppressive drug cyclosporin (CsA). The dosage of CsA is complicated by the large intra- and interindividual variability in its pharmacokinetics, as well as by the narrow concentration range between insufficient immunosuppression and toxicity.Potential sources of error in the sampling procedure and the advantages and disadvantages of the available analytical methods are discussed. Traditionally, 12 or 24 hour trough concentrations of CsA are monitored. Recently, peak concentrations or estimation of AUCs by a limited sampling strategy have been tried to improve the relatively weak concentration-effect and concentration-toxicity relationships found with trough CsA concentration monitoring.Studies of the CsA concentration-effect relationships for various treatment indications are reviewed.This review is based on parts of a PhD thesis presented by the author in April 1990. Reprints of the thesis may be requested from the authorMetabolites 1, 17, 18, 21 and 26 (old nomenclature, used in text) correspond to M9, M1, M1c, M4N, M1c9 according to the new nomenclature proposed by Wenger (1990)     

Therapeutic drug monitoring to adjust dosing in morbid obesity - a new use for an old methodology

The phenomena of hunger and need at one end of the spectrum and obesity and plenty on the other is an anomaly of the 21(st) century, likely to be due to a combination of distributive inequities in food, social justice, access to education and other socio-economic factors. Both are major problems worldwide, although obesity has more media coverage due to the exponentially increasing incidence and the huge social and economic burden this is placing on Western society. For example, prevalence rates of obesity are currently exceeding 30% of adults in the USA with direct morbidity and mortality complications, in addition to the additional obesity-related health problems and death. Obesity is also rising in children. Obese people are thus a sizable group, and as with those with altered renal or liver function, require specific consideration with respect to the appropriate dosing of medications. However guidelines for how to do this in obesity are not currently available, due to the paucity of literature and regulatory rules for new medications which usually only request the demonstration of average population effectiveness. We believe it is timely for regulatory agencies worldwide to mandate studies involving consideration of body size, particularly obesity, in approving new medications across the therapeutic spectrum. This will drive the pharmaceutical industry to consider these groups in studies and will encourage investigator-initiated research using therapeutic drug monitoring (TDM), target concentration therapy (TCI) and pharmacogenetic (PGx) studies to optimize drug dosing.     

A pharmacoeconomic analysis of the impact of therapeutic drug monitoring in adult patients with generalized tonic-clonic epilepsy

AIMS: To carry out a retrospective pharmacoeconomic analysis of the impact of therapeutic drug monitoring (TDM) in adult patients with generalized tonic-clonic epilepsy in an academic, non profit making organization. METHODS: Twenty-five patients who had undergone TDM were compared with 25 age, disease and duration of drug therapy matched controls who had not undergone TDM. Only direct costs were calculated. These included cost to the hospital of providing the TDM service, cost to the hospital per seizure saved, and cost to the patient per seizure saved. RESULTS: Patients undergoing TDM had much more effective seizure control (P = 0.00032, OR 4.846, 95% confidence interval 1.29,18.3), fewer adverse events, better earning and were more likely to be married than the control group. CONCLUSIONS: In patients with adult onset epilepsy, a minimum of two drug estimations per year offers significant benefit in terms of better seizure control, fewer adverse events and greater chances of remission.     

Therapeutic drug monitoring of psychotropic medications

Therapeutic drug monitoring (TDM) of a number of psychotropic medications has proven to be of value, enabling minimization of the limitations of considerable genetic variability in their metabolism and the high rates of poor compliance with many psychiatric disorders. Therapeutic ranges have been established for lithium, some of the tricyclic antidepressants, and clozapine. TDM has also been shown to be useful in avoiding toxicity (as many psychotropics have narrow therapeutic indices), particularly that due to interactions with other compounds.     

Therapeutic drug monitoring of psychotropic medications

Therapeutic drug monitoring (TDM) of a number of psychotropic medications has proven to be of value, enabling minimization of the limitations of considerable genetic variability in their metabolism and the high rates of poor compliance with many psychiatric disorders. Therapeutic ranges have been established for lithium, some of the tricyclic antidepressants, and clozapine. TDM has also been shown to be useful in avoiding toxicity (as many psychotropics have narrow therapeutic indices), particularly that due to interactions with other compounds.     

Therapeutic drug monitoring of atazanavir: surveillance of pharmacotherapy in the clinic

BACKGROUND: Therapeutic failure with antiretroviral therapy (ART) is a substantial issue where viral rebound, viral resistance and drug-related toxicity remain serious concerns. Drug exposure-response relationships have been described for the protease inhibitors, pharmacokinetic variability is substantial for this class of drugs and drug interactions can also alter ART exposure. Given this background we established a therapeutic drug monitoring (TDM) service to monitor atazanavir (ATV) plasma concentrations early after the therapy was made available to treatment-experienced people infected with HIV who were managed in a clinical setting. METHODS: This was a prospective observational study which evaluated plasma samples from 110 highly treatment-experienced people with HIV using TDM and applied pharmacokinetic analysis over a five month period. RESULTS: ATV trough concentrations exhibited substantial intersubject variability (<25-2108 microg l(-1)). A substantial number of subjects (50%,13/26) who received ATV400 mg daily had low exposure to ATV. Serum bilirubin concentrations correlated significantly with higher ATV trough concentrations (rho = 0.803; P < 0.001) and 55% (29/53) of subjects who received ATV300/100 mg RTV daily had plasma concentrations above a proposed target concentration associated with elevated bilirubin concentrations. This study confirmed low ATV exposure in eight subjects with HIV receiving ATV 400 mg daily. Reasons for low ATV exposure in this cohort include administration of interacting drugs, including a possible interaction with ritonavir, fluticasone and ATV, impaired ATV absorption secondary to suspected achlorhydria and potential interactions with colchicine and nandrolone. Viral load remained undetectable in most of these subjects with low ATV exposure. CONCLUSIONS: TDM and targeted pharmacokinetic studies should be viewed as fundamental tools in the development and clinical application of ART, to improve pharmacotherapy for people with HIV.