Therapeutic drug monitoring of antiretroviral drugs in HIV-infected patients

Introduction: Therapeutic drug monitoring (TDM) may be beneficial when applied to antiretroviral (ARV). Even though TDM can be a valuable strategy in HIV management, its role remains controversial.

Areas covered: This review provides a comprehensive update on important issues relating to TDM of ARV drugs in HIV-infected patients. Articles from PubMed with keywords relevant to each topic section were reviewed. Search strategies limited to articles published in English.

Expert commentary: There is evidence supporting the use of TDM in HIV treatment. However, some limitations need to be considered. The evidence supporting the use of routine TDM for all patients is limited, as it is not clear that this strategy offers any advantages over TDM for selected indications. Selected groups of patients including patients with physiological changes, patients with drug-drug interactions or toxicity, and the elderly could potentially benefit from TDM, as optimized dosing is challenging in these populations.     

Therapeutic monitoring of the new antiepileptic drugs

Objective: To discuss the potential value of therapeutic drug monitoring (TDM) of the new antiepileptic drugs gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide. Methods: A review of studies of the relationship between plasma concentrations and effects of new antiepileptic drugs is provided. Furthermore, the potential value of TDM of these drugs is discussed in relation to their mode of action and their pharmacokinetic properties. The various methods that are available for analysing plasma concentrations of the new antiepileptic drugs are also briefly reviewed. Results: The available information on the relationship between plasma concentrations and effects of the new drugs is scarce. For most drugs, wide ranges in concentrations associated with seizure control are reported, and a considerable overlap with drug levels among non-responders and also with concentrations associated with toxicity is often noted. However, very few studies have been designed primarily to explore the relationship between drug plasma concentrations and effects. Consequently, there are no generally accepted target ranges for any of the new antiepileptic drugs. Although the available documentation clearly is insufficient, the pharmacological properties of some of the drugs, in particular lamotrigine, zonisamide and, possibly, oxcarbazepine, topiramate and tiagabine, suggest that they may be suitable candidates for TDM. Conclusion: TDM of some of the new antiepileptic drugs may be of value in selected cases, although routine monitoring in general cannot be recommended at this stage. Further systematic studies designed specifically to investigate concentration–effect relationships of the new antiepileptic drugs are urgently needed. Received: 16 September 1999 / Accepted in revised form: 9 October 1999     

抗癫痫药物监测的规范化实践

目的：探讨抗癫痫药（AEDs）治疗监测的规范化体系。方法：对常用抗癫痫药卡马西平、苯妥因、苯巴比妥、扑米酮和丙戊酸的血药浓度开展规范化监测。结果：AEDs治疗监测应明确监测指征,做好样品的采集和血药浓度测定,及时报告监测结果,并给予简明的分析、解释及具体建议。结论：建立AEDs治疗监测的规范化质量保证体系,对抗癫痫治疗可起到积极的作用。     

血药浓度监测良好工作模式探讨

本文通过具体实践,结合工作中的具体情况和问题,对血药浓度监测中的常见问题和注意事项以及良好工作模式进行了深入地思考与探讨,以期对建立血药浓度监测的良好工作模式有所帮助,从而保证临床用药的安全合理。     

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: 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 – 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.     

我院2012年7种治疗药物监测结果回顾性分析

目的：对医院2012年1~12月7种治疗药物监测（TDM）的结果进行回顾性分析,探讨治疗药物监测在临床上的应用价值。方法应用均相酶放大免疫分析法（EMIT）测定他克莫司、环孢素、苯妥英钠、卡马西平、丙戊酸、苯巴必妥、万古霉素7种药物的血药浓度,并对测定结果进行分析总结。结果他克莫司和环孢素在肾移植术后抗排斥治疗中需要密切监测药物疗效和调整药物剂量。抗癫痫药的 TDM 未引起足够的重视,其中苯妥英钠出现中毒反应最多。万古霉素的临床送检量最少,与临床使用量少和血药浓度是否需要监测存在争议性有关。结论开展血药浓度监测,能减少药源性疾病的发生,提高癫痫患者的生活质量,保证患者用药安全有效。     

治疗药物监测的研究进展

本文对治疗药物监测的药物如中药、抗癫痫药、免疫抑制药、抗逆转录病毒药物、抗精神病药物、抗肿瘤药物和抗微生物药物的最新研究进展进行综述,介绍其方法学上的最新进展,如利用液质联用将成为发展方向。结合群体药动学和药物遗传学的最新发展,研究疾病药物治疗中的新方法,指导临床个体化用药,提出治疗药物监测(TDM)新的发展方向,如利用基因分型和基因芯片对患者测定基因型,以指导临床合理用药。     

Quality control in therapeutic drug monitoring

Quality control of routine drug assays, like most immunoassays, should mainly be the responsibility of each individual laboratory: intra-laboratory quality control. External quality assessment should direct its efforts in particular to non-routine methods and to new assays. However, it may sometimes also be very useful to have laboratory results of routine assays studied in external programmes, since vague requests or difficult interpretations of drug concentrations need discussion outside the individual laboratory.     

常用免疫抑制剂人血中定量监测方法研究进展

免疫抑制剂在临床上主要用于治疗自身免疫性疾病和预防脏器移植排斥。免疫抑制剂的使用需要进行治疗药物监测,其检测结果通常作为临床医生调整用药剂量的重要依据之一。本文就目前临床常用的免疫抑制剂他克莫司、环孢素、霉酚酸酯、糖皮质激素及新型免疫抑制剂西罗莫司和依维莫司在人血中浓度的检测方法作一综述,以供参考。     

抗肿瘤药物的治疗药物监测研究

尽管治疗药物监测(TDM)已广泛应用于多个疾病治疗领域,但在抗肿瘤药物方面的应用仍较为局限。近年来,抗肿瘤药物的暴露量与其疗效和药物不良反应之间的相关性研究越来越多,这有利于抗肿瘤药物个体化精准给药。本文综述了细胞毒类和靶向性(小分子和大分子)抗肿瘤药物的治疗药物监测现状,为肿瘤药物个体化用药提供参考。     

A survey of therapeutic drug monitoring services in Malaysia

In Malaysia, therapeutic drug monitoring (TDM) service was started in the 1980s. Since then, the number of hospitals that offer the service has increased. In this paper, we report the findings of a nationwide survey describing the practice of TDM in these hospitals. Questionnaires were mailed to 128 government hospitals. Data were collected for general characteristics of the hospitals, administrative, and laboratory activities related to TDM service. One hundred and twenty-one hospitals responded to the survey. Thirty-four hospitals (28.1%) provided the service with their own TDM laboratories, 44 hospitals (36.4%) provided the service using other hospitals’ laboratories and 43 hospitals (35.5%) did not provide the service at all. TDM services were more likely to be offered in larger hospitals with various medical specialties. Since it is managed entirely by hospital pharmacists, these pharmacists assume an important role in ensuring optimum use of the TDM service.     

64例老年患者万古霉素血药浓度监测结果分析

目的:通过分析64例老年肺部感染患者万古霉素血药浓度的监测结果,为临床合理用药提供参考.方法:采用荧光偏振免疫法测定万古霉素的血药浓度,对64例157例次血药浓度监测结果进行比较分析.结果:患者万古霉素血清峰浓度和谷浓度均在治疗窗范围内的仅占40% 左右,而谷浓度高于正常范围及峰浓度低于正常范围的约占50% ;首剂饱和方案组与首剂未饱和方案组中血清峰浓度比较有显著性差异,而谷浓度无显著性差异;肾功能正常组患者用药前、后内生肌酐清除率有显著性差异,尿素氮无显著性差异,而肾功能损害组患者用药前、后尿素氮及内生肌酐清除率均无显著性差异;近45% 的患者给药方案为500 mg,每日2~3 次,约75% 的患者未能达到有效峰浓度,约60% 的患者谷浓度超过正常水平.结论:老年感染患者使用万古霉素个体差异很大且多数患者伴有肾功能轻中度损害,应尽量给予首剂饱和方案并对其进行血药浓度监测,以利于实现个体化给药,进而提高该药应用的有效性和安全性.     

儿童3种免疫抑制药的药物监测

免疫抑制剂是一类特殊的专科用药,虽然在儿童中应用较成人少,但药品的作用机制导致不良反应发生率高,许多免疫抑制剂在药动学和药效学上又存在着明显的个体差异,所以对服用免疫抑制剂的儿童患者,药物监测同样需得到重视。本文选取了最有代表性的微生物来源免疫抑制剂,分别对其药物特点、适应证以及可行的分析方法进行综述,希望对开展儿童免疫抑制药物的治疗监测起到借鉴作用。     

治疗药物监测概况及研究进展

通过查阅有关书籍和近年国内外的文献资料,回顾治疗药物监测(TDM)的发展与现状,介绍目前进行TDM的药物种类和常用技术方法,展望遗传药理学在个体化用药中的应用前景。未来的治疗药物监测模式是传统模式和药物遗传学监测相结合,进一步完善个体给药方案的制定。     

ICU患者替考拉宁给药方式及药物浓度监测的临床意义探讨

目的:探讨替考拉宁的合理给药方式及进行治疗药物浓度监测(TDM)的必要性。方法:对使用替考拉宁治疗的20例重症感染患者的临床资料进行回顾性分析,按照治疗前3 d平均起始给药剂量(MID)的不同,分为MID=533.33 mg/d组10例和MID<533.33 mg/d组10例,所有患者治疗期间采集血样,应用高效液相色谱法(HPLC)测量替考拉宁血药谷浓度(Cmin)。结果:研究发现替考拉宁Cmin与初始给药剂量密切相关,其Pearson相关性为0.685,双侧显著性检验均为0.01,使用起始负荷剂量的患者Cmin明显高于不采用起始负荷量的患者(P<0.01),且治疗效果亦明显好于不予以起始负荷量的患者(P<0.01),两组病人的药物不良反应发生率差异无统计学意义。结论:重症监护病房(ICU)患者在使用替考拉宁时需要予以规范的起始负荷给药方式,以期快速达到有效药物治疗浓度,取得良好的治疗效果,同时应根据TDM结果协助调整给药剂量,避免替考拉宁药物不良反应的发生。     

重症感染患者替考拉宁药物浓度监测的临床意义探讨

目的探讨重症感染患者进行替考拉宁药物浓度监测的临床意义。方法对30例重症感染患者的临床资料进行回顾性分析,根据替考拉宁治疗前3d平均起始给药剂量(MID)的不同,分为MID=533.33mg/d组和MID<533.33mg/d组,所有患者治疗期间采集血样,应用高效液相色谱法测量血药谷浓度。结果替考拉宁Cmin水平与MID密切相关,Pearson相关性为0.678,双侧显著性检验均为0.01,使用起始负荷剂量的患者Cmin明显高于不采用起始负荷量的患者(P<0.01),且治疗效果亦明显好于不予以起始负荷量的患者(P<0.01),两组患者的药物不良反应发生率无明显统计学差异。结论重症感染患者在使用替考拉宁时需要予以规范的负荷给药方式,以期快速达到有效药物治疗浓度,同时应予以治疗药物浓度监测,协助调整给药剂量,避免药物不良反应的发生。     

基于伏立康唑血药浓度监测的药物相互作用研究

目的 临床药师通过治疗药物监测(TDM)手段，研究利福平和伏立康唑之间的药物相互作用。方法 基于利福平和伏立康唑联用，及停用利福平后使用伏立康唑这两类患者的伏立康唑血药浓度监测情况，揭示利福平和伏立康唑间的药物相互作用强度与持续时间。结果 18例利福平和伏立康唑联用患者，94.44%患者的伏立康唑血药浓度低于有效治疗浓度范围下限(1.0mg/L)，其中72.22%患者低于定量下限0.16mg/L；19例停用利福平后再使用伏立康唑的标本中，停药6d内伏立康唑血药浓度小于1.0mg/L共12例，占总例数的63.16%，占停药6d内例数的91.67%；停药7d及以上伏立康唑血药浓度大于1mg/L的5例，占总例数的26.32%，占停药7d及以上例数的83.33%。结论 利福平会严重降低伏立康唑血药浓度，在停用利福平第7d起伏立康唑血药浓度很可能才上升有效浓度范围，因此临床上应避免伏立康唑与利福平联用。临床药师借助TDM成功干预了有临床意义的药物相互作用，TDM是临床药师参与药物治疗的有效技术手段。     

Therapeutic drug monitoring of cytotoxic drugs

Therapeutic drug monitoring is not routinely used for cytotoxic agents. There are several reasons, but one major drawback is the lack of established therapeutic concentration ranges. Combination chemotherapy makes the establishment of therapeutic ranges for individual drugs difficult, the concentration-effect relationship for a single drug may not be the same as when that drug is used in a drug combination. Pharmacokinetic optimization protocols for many classes of cytotoxic compounds exist in specialized centres, and some of these protocols are now part of large multicentre trials. Nonetheless, methotrexate is the only agent which is routinely monitored in most treatment centres. An additional factor, especially in antimetabolite therapy, is the existence of pharmacogenetic enzymes which play a major role in drug metabolism. Monitoring of therapy could include assay of phenotypic enzyme activities or genotype in addition to, or instead, the more traditional measurement of parent drug or drug metabolites. The cytotoxic activities of mercaptopurine and fluorouracil are regulated by thiopurine methyltransferase (TPMT) and dihydropyrimidine dehydrogenase (DPD), respectively. Lack of TPMT functional activity produces life-threatening mercaptopurine myelotoxicity. Very low DPD activity reduces fluorouracil breakdown producing severe cytotoxicity. These pharmacogenetic enzymes can influence the bioavailability, pharmacokinetics, toxicity and efficacy of their substrate drugs.