Current status of therapeutic drug monitoring for immunosuppressive drugs

Therapeutic drug monitoring(TDM) is advocate to provide information about the adequacy of a dosing regimen or likelihood of toxicity associated with drug. Such situations include large intra- and inter-individual variabilities in pharmacokinetics; correlation between drug concentrations and toxicity or between concentrations and efficacy; narrow therapeutic interval, meaning toxic symptoms close to concentration with full therapeutic effect; and absence of appropriate parameter to recognize pharmacological effect. Current clinical immunosuppressive regimens consist of combinations of drugs, to allow a reduction in the individual drug doses as a means widening the therapeutic interval and reduction the likelihood of individual drug toxicity. With the recent introduction of new immunosuppressive drugs, there is an unprecedented interest in TDM for immunosuppressive drugs. In this review I discuss the current status of pharmacokinetic monitoring for cyclosporine, tacrolimus and mycophenolate mofetil.     

Pharmacokinetics-pharmacodynamics of antifungal drugs. Consequences for therapeutic drug monitoring

Despite pharmacokinetic-pharmacodynamic relationships were clearly evidenced for antifungal drugs by the use of experimental models, few target plasma concentrations could be determined from studies performed in patients. The main causes explaining this lack of data are reviewed and the possible use in humans of the parameters obtained from animal models is discussed.     

Office therapeutic drug monitoring

Considerations necessary for appropriate therapeutic drug monitoring in the office practice setting have been presented. Practical issues focusing on clinical pharmacokinetics as well as serum drug concentration evaluation methods and techniques have been reviewed, with emphasis on orally administered medications.     

Voriconazole therapeutic drug monitoring

We report on 28 patients who underwent voriconazole monitoring because of disease progression or toxicity. A relationship (P<0.025) between disease progression and drug concentration was detected. Favorable responses were observed in 10/10 patients with concentrations above 2.05 microg/ml, while disease progressed in 44% (n=18) of patients with concentrations below 2.05 microg/ml.     

Computer-assisted therapeutic drug monitoring

The computer is a powerful technology that has been applied to many aspects of the practice of medicine. This report describes how the computer may enhance the process for therapeutic drug monitoring by coordination, control, and education of the medical care team.     

Application of pharmacokinetic modelling to the routine therapeutic drug monitoring of anticancer drugs

Over the last 10 years, proofs of the clinical interest of therapeutic drug monitoring (TDM) of certain anticancer drugs have been established. Numerous studies have shown that TDM is an efficient tool for controlling the toxicity of therapeutic drugs, and a few trials have even demonstrated that it can improve their efficacy. This article critically reviews TDM tools based on pharmacokinetic modelling of anticancer drugs. The administered dose of anticancer drugs is sometimes adjusted individually using either a priori or a posteriori methods. The most frequent clinical application of a priori formulae concerns carboplatin and allows the computation of the first dose based on biometrical and biological data such as weight, age, gender, creatinine clearance and glomerular filtration rate. A posteriori methods use drug plasma concentrations to adjust the subsequent dose(s). Thus, nomograms allowing dose adjustment on the basis of blood concentration are routinely used for 5-fluorouracil given as long continuous infusions. Multilinear regression models have been developed, for example for etoposide, doxorubicin. carboplatin, cyclophosphamide and irinotecan, to predict a single exposure variable [such as area under concentration-time curve (AUC)] from a small number of plasma concentrations obtained at predetermined times after a standard dose. These models can only be applied by using the same dose and schedule as the original study. Bayesian estimation offers more flexibility in blood sampling times and, owing to its precision and to the amount of information provided, is the method of choice for ensuring that a given patient benefits from the desired systemic exposure. Unlike the other a posteriori methods, Bayesian estimation is based on population pharmacokinetic studies and can take into account the effects of different individual factors on the pharmacokinetics of the drug. Bayesian estimators have been used to determine maximum tolerated systemic exposure thresholds (e.g. for topotecan or teniposide) as well as for the routine monitoring of drugs characterized by a very high interindividual pharmacokinetic variability such as methotrexate or carboplatin. The development of these methods has contributed to improving cancer chemotherapy in terms of patient outcome and survival and should be pursued.     

Glucuronidation in therapeutic drug monitoring

BACKGROUND: Glucuronidation is a major drug-metabolizing reaction in humans. A pharmacological effect of glucuronide metabolites is frequently neglected and the value of therapeutic drug monitoring has been questioned. However, this may not always be true. METHODS: In this review the impact of glucuronidation on therapeutic drug monitoring has been evaluated on the basis of a literature search and experience from the own laboratory. RESULTS: The potential role of monitoring glucuronide metabolite concentrations to optimize therapeutic outcome is addressed on the basis of selected examples of drugs which are metabolized to biologically active/reactive glucuronides. Furthermore indirect effects of glucuronide metabolites on parent drug pharmacokinetics are presented. In addition, factors that may modulate the disposition of these metabolites (e.g. genetic polymorphisms, disease processes, age, and drug-drug interactions) are briefly mentioned and their relevance for the clinical situation is critically discussed. CONCLUSION: Glucuronide metabolites can have indirect as well as direct pharmacological or toxicological effects. Although convincing evidence to support the introduction of glucuronide monitoring into clinical practice is currently missing, measurement of glucuronide concentrations may be advantageous in specific situations. If the glucuronide metabolite has an indirect effect on the pharmacokinetics of the parent compound, monitoring of the parent drug may be considered. Furthermore pharmacogenetic approaches considering uridine diphosphate (UDP) glucuronosyltransferases polymorphisms may become useful in the future to optimize therapy with drugs subject to glucuronidation.     

Immunoassays in therapeutic drug monitoring

Numerous immunoassay methods are now in routine use for therapeutic drug monitoring of drugs and metabolites. Most methods are homogeneous immunoassays with excellent specificity, accuracy, and precision. In addition, these assays are readily automated, and commercial versions of theses reagents are available with dedicated instrumentation. This report reviews current methods and systems and discusses methodology that has been developed for physician office or other nontraditional settings.     

Chromatographic techniques for therapeutic drug monitoring

Although GLC is still used with some frequency, HPLC is currently the most widely practiced chromatographic technique for the measurement of therapeutic drugs. Efficiency and selectivity can be manipulated to meet the requirements of clinical samples, especially when drug metabolites are present and their concentrations are of importance. The ability to simultaneously quantitate several drugs has led to the development of many methods for antiepileptic, antiarrhythmic, and antidepressant drugs. Selective detectors offer more sensitive analysis in many separations and are increasingly popular. The development of automated methods for sample preparation suggests that more cost-effective strategies for the chromatographic analysis of new drugs will be possible in the near future.     

Issues in therapeutic drug monitoring evaluation

A reassessment of the interest of therapeutic drug monitoring (TDM) is needed for a better definition of its applications. It rests on the hypothesis of the existence of an interindividual variability of the dose-effect relationship, this variability being influenced by pharmacokinetic variability. Different types of endpoints were used in validation studies (pharmacokinetic, indirect, economic) and few studies have used clinical endpoints. The question should be: does TDM allow for a better dose adjustment than one based only on criteria other than drug concentration? Retrospective studies have a 'diagnostic test' approach and only prospective clinical trials will provide a real validation. Factors which limit the setting up of such studies are: the number of subjects to include, the often imprecise measurement of drug exposure and poor knowledge of the pharmacokinetic-pharmacodynamic relationship and its variability.     

万古霉素血药浓度监测的临床应用

目的：通过监测万古霉素血药浓度,分析血药浓度与疗效、药物不良反应的关系,指导万古霉素在耐甲氧西林葡萄球菌（M RS ）等革兰阳性球菌感染中的合理用药。方法在有指征应用万古霉素的M RS等革兰阳性球菌感染患者中进行该药药物浓度监测。留取血样时间为万古霉素给药至少4个剂量后,在给药前30 min内采血送检谷浓度,给药结束后30 min至1 h内采血送检峰浓度,采用荧光偏振免疫法测定万古霉素血药浓度,同时收集临床资料,进行统计分析。结果25例患者万古霉素血药谷浓度为3．22-50．79 mg／L ,谷浓度＜5 mg／L者3例,5-＜10 mg／L者11例,10-15 mg／L者3例,＞15 mg／L者8例;峰浓度为13．57-60．47 mg／L ,峰浓度＜25 mg／L者14例,25-40 mg／L者7例,＞40 mg／L者4例。感染患者临床好转率为80．0％（20／25）;细菌清除率为87．5％（21／24）。13例患者根据血药浓度监测结果调整用药剂量,其治疗好转率为92．3％（12／13）。4例患者出现肾功能损害。结论万古霉素血药浓度个体差异较大,通过监测血药浓度制定的万古霉素个体化给药方案用于治疗M RS等革兰阳性球菌感染可提高治愈率,减少药物不良反应。     

Instrumentation and techniques for therapeutic drug monitoring

This article describes and compares the predominant systems for performing therapeutic drug monitoring. Advantages and disadvantages, costs, and future trends are noted. Useful information for the initiation or expansion of this clinical service is provided.     

Establishing a therapeutic drug monitoring consultation service

A formal therapeutic drug monitoring consultation service (TDMCS) will enhance the clinical benefits of drug level determinations. It can result in decreased length of stay and improved risk management posture. The successful implementation of a TDMCS requires the coordinated efforts of a multidisciplinary team that may include physicians, pharmacists, nurses, and laboratory personnel. Clinical pathologists and clinical pharmacists are particularly well qualified to direct a TDMCS. Consistent delivery of quality services requires that all procedures related to the consultation process be standardized and documented in a procedures manual. The cost of providing the service may be recovered through both direct and indirect mechanisms.     

Special considerations for geriatric therapeutic drug monitoring

Numerous physiological changes during the normal aging process can potentially affect how drugs are handled by the body. Gastrointestinal changes include increased gastric pH, decreased intestinal motility, and decreased blood perfusion. Age-related changes in body composition and protein concentrations in plasma contribute to alterations in the distribution of drugs. Hepatic metabolism of drugs may be affected, and renal excretion via glomerular filtration or tubular secretion is diminished. The importance of each of these physiological changes in the elderly, as well as the contribution of multi-drug therapy and other external factors, is discussed.