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.     

Therapeutic drug monitoring of everolimus using the dried blood spot method in combination with liquid chromatography–mass spectrometry

An assay of everolimus based on finger prick sampling and consecutive application as a blood spot on sampling paper has been developed. We explored several methods [K. Hoogtanders, J. van der Heijden, M. Christiaans, P. Edelbroek, J. van Hooff, L. Stolk, J. Pharm. Biomed. Anal. 44 (2006) 658–664; A. Allanson, M. Cotton, J. Tettey, et al., J. Pharm. Biomed. Anal. 44 (2007) 963–969] and developed a new method, namely the impregnation of sampling paper with a solution of plasma–protein, formic acid and ammonium acetate, in combination with the extraction of the blood spot by filter filtration. This kind of sample preparation provides new possibilities for blood spot sampling especially if analytes are adsorbed to the paper.The dried blood spot was analysed using the HPLC–electrospray-tandem mass spectrometry method, with 32-desmethoxyrapamycin as the internal standard. The working range of our study was 2–30 μg/l. Within this range, intra-and inter-assay variability for precision and accuracy was <15%. Everolimus blood spot samples proved stable for 3 days at 60 °C and for 32 days at 4 °C. Everolimus concentrations of one stable out-patient were compared after both blood spot sampling and conventional venous sampling on various occasions. Results indicate that this new method is promising for therapeutic drug monitoring in stable renal transplant patients.     

骨髓移植患者术后环孢素血药浓度监测

目的:探讨异基因骨髓移植患者术后环孢素(CsA)的血药浓度与移植物抗宿主病(GVHD)和药物相关毒性之间的关系。方法:采用荧光偏振免疫分析法(FPIA),对28例骨髓移植患者术后全血谷浓度进行监测,共252例次,并对监测结果进行分析。结果:28例骨髓移植患者252例次监测结果提示,有效浓度为100～400μg.L-1。当浓度>400μg.L-1时,药品不良反应(ADR)发生率增加为16.28%;当浓度<100μg.L-1时,GVHD率增加为27.27%。结论:及时监测CsA浓度,根据动态监测结果制订个体化给药方案,才能减少GVHD以及ADR的发生,提高移植后的成功率。     

中药TDM及其在个体化给药方案中的应用

目的近年来有关中药不良反应的报道逐年增多,中药TDM成为减少中药使用中药品不良反应有效的方法,本文综述了中药治疗药物监测的使用范围,试验方法以及在中药个体化给药方案制定中的应用.     

Impact of sampling time deviations on the prediction of the area under the curve using regression limited sampling strategies

The regression limited sampling strategy approach (R‐LSS), which is based on a small number of blood samples drawn at selected time points, has been used as an alternative method for the estimation of the area under the concentration–time curve (AUC). However, deviations from planned sampling times may affect the performance of R‐LSS, influencing related therapeutic decisions and outcomes. The aim of this study was to investigate the impact of different sampling time deviation (STD) scenarios on the estimation of AUC by the R‐LSS using a simulation approach. Three types of scenarios were considered going from the simplest case of fixed deviations, to random deviations and then to a more realistic case where deviations of mixed nature can occur. In addition, the sensitivity of the R‐LSS to STD in each involved sampling point was evaluated. A significant impact of STD on the performance of R‐LSS was demonstrated. The tolerance of R‐LSS to STD was found to depend not only on the number of sampling points but more importantly on the duration of the sampling process. Sensitivity analysis showed that sampling points at which rapid concentration changes occur were relatively more critical for AUC prediction by R‐LSS. As a practical approach, nomograms were proposed, where the expected predictive performance of R‐LSS was provided as a function of STD information. The investigation of STD impact on the predictive performance of R‐LSS is a critical element and should be routinely performed to guide R‐LSS selection and use. Copyright © 2015 John Wiley & Sons, Ltd.     

375例次血药浓度监测分析及临床意义

目的：对2004年8月-2005年8月间我院常规药物浓度监测的六个品种进行分析，探讨治疗药物监测（简称TDM）在临床上更广泛的应用价值。方法：应用均相酶免疫法测定药物浓度，分析六种药物的药物浓度测定结果，考察六种药物的监测目的。结果：监测药物浓度例数共375例．其中监测目的用于判断是否中毒的13例次．判断是否曾用过该药物的55例次，判断疗效及调整剂量的286例次，去除毒物过程监测的21例次。地高辛是六种药物中高于有效浓度例数最多的一种药物，也是出现临床中毒反应最多的一种药物，因此是最需要监测使用的药物品种之一。结论：治疗药物监测并不仅仅能监测药物疗效和调整药物剂量，而且在临床的诊断和治疗方面能协助临床解决更多实际问题。     

Treatment option for sepsis in children in the era of antibiotic resistance

Sepsis caused by multidrug-resistant microorganisms is one of the most serious infectious diseases of childhood and poses significant challenges for pediatricians involved in management of critically ill children. This review discusses the use of pharmacokinetic/dynamic principles (i.e., prolonged infusion of β-lactams and vancomycin, once-daily administration of aminoglycosides and rationale of therapeutic drug monitoring) when prescribing antibiotics to critically ill patients. The potential of ‘old’ agents (i.e., colistin, fosfomycin) and newly approved antibiotics is critically reviewed. The pros and cons of combination antibacterial therapy are discussed and finally suggestions for the treatment of sepsis caused by multidrug-resistant organisms are provided.     

临床药师参与1例车祸致重症感染患者临床治疗万古霉素谷浓度不达标的原因分析

目的:分析车祸致重症感染患者万古霉素谷浓度不达标的原因,探究临床药师的药学监护过程。方法:临床药师参与万古霉素给药方案的制订,对重症感染患者开展治疗药物监测(TDM)和药学服务。结果:万古霉素的血药浓度受患者体质量、年龄、肾功能、体液量及表观分布容积等多种因素的影响。结论:万古霉素的个体差异较大,影响因素较多,临床医生和药师应对万古霉素TDM,关注其谷浓度的变化。     

柱切换HPLC法测定5—Fu血药浓度

采用柱切换HPLC法建立5—Fu血药浓度测定方法,并用于治疗药物浓度监测。3例病人的测定结果,T_(1/2)为25±6.71min,Vd为0.32±0.11L/kg。