Therapeutic drug monitoring of sertraline: variability factors as displayed in a clinical setting

This report describes sertraline pharmacokinetics derived from routine therapeutic drug monitoring (TDM) data. A high-performance liquid chromatographic method with ultraviolet detection was established for routine sertraline TDM, and 924 analyses were performed from April 1995 to May 1997. Extensive predefined inclusion/exclusion criteria were applied to increase the validity of scientifically evaluated data. Subsequently, 605 samples (65.5%) were excluded. The remaining 319 samples from 319 patients, representative of steady state trough specimens and accompanied by essential clinical information provided on request forms, were scrutinized. A pronounced interindividual variability was observed. Smokers had significantly lower concentration-to-dose (C/D) mean ratios of serum sertraline (s-sert) and its main metabolite desmethylsertraline (s-dsert) than nonsmokers. Higher s-sert and s-dsert C/D mean ratios were found in elderly patients than in adults aged less than 65 years. In a subset of 20 patients in whom repeated TDM analyses were performed, observed intraindividual sertraline TDM outcome variability was low. The results highlight sertraline TDM as a tool for individual dose optimization and evaluation of patient drug compliance as well as drug-drug interactions.     

Therapeutic drug monitoring data: risperidone does not increase serum clozapine concentration

BACKGROUND: Two case reports suggest that serum clozapine concentration may increase when risperidone is added to clozapine treatment. However, risperidone is not a significant inhibitor of the most important clozapine metabolising cytochrome P(450) (CYP) enzymes (e.g. CYP1A2). OBJECTIVE: To study whether serum clozapine concentrations are affected by risperidone. METHODS: Intraindividual comparison of serum clozapine therapeutic drug monitoring data from 18 patients during and without risperidone use. RESULTS: Addition of risperidone (mean +/-SD dose 2.9+/-0.9 mg/day, range 2-4 mg/day) to clozapine treatment (mean clozapine dose 451+/-207 mg/day) did not result in any significant changes in serum clozapine concentration or clozapine concentration/dose (C/D) ratio relative to the values without risperidone (mean clozapine dose 437+/-168 mg/day). During risperidone use mean serum clozapine concentration was 3% (P=0.75) and C/D ratio 8% (P=0.46) lower than without concomitant risperidone. The mean ratio mu(test)/mu(reference) for clozapine C/D ratios was 0.99 (90% CI 0.82-1.15), confidence interval being within the equivalence interval of 0.80-1.25. CONCLUSIONS: Risperidone does not affect serum clozapine concentrations to any significant degree.     

新免疫抑制剂的治疗药物监测

随着器官移植技术的发展和广泛应用,免疫抑制剂受到越来越多的关注。免疫抑制剂通过抑制淋巴细胞的功能,减少移植排斥反应的发生,延长移植物存活时间。但由于本身具有较强的毒性,尤其是肾毒性,因此常常需要在低剂量发生移植排斥和高剂量产生毒性之间取得平衡。除了经典的如肾上腺皮质激素、环磷酰胺、硫唑嘌呤等细胞毒药物外,新一代免疫抑制剂环孢素A、霉酚酸脂、他克莫司、西罗莫司等由于其治疗窗窄,即治疗浓度与中毒浓度接近;药代动力学存在明显的个体内及个体之间的差异,因此需要密切监测药物浓度,以确保药物处于有效治疗范围,且不易中…     

治疗药物监测的概念探析

治疗药物监测主要是通过实现临床药物治疗个体化,提高药物的临床有效性和安全性。在我国,治疗药物监测工作开展已经历30余年的历程,可查阅有关治疗药物监测的概念,其表述却不尽相同,各有侧重点。而一个学科概念或定义对该学科发展至关重要。为了促进治疗药物监测发展,本文查阅国内外有关治疗药物监测相关的历史文献,总结其发展过程,以期为规范治疗药物监测概念提供参考。     

Development of a simple and rapid method to measure the free fraction of lamotrigine in plasma using HPLC: applications for therapeutic drug monitoring

Lamotrigine (LTG) is a widely used antiepileptic drug (AED) for the treatment of new-onset, as well as refractory epilepsy. Due to the narrow treatment window and large individual variability in the pharmacokinetics and pharmacodynamics of LTG, therapeutic drug monitoring (TDM) is necessary in clinical practice to guide dose adjustments. Individual differences and drug combinations can also affect protein binding rate, which further affects the unbound concentration of LTG. The unbound fraction is more closely related to adverse reactions and therapeutic efficacy than total concentration. Therefore, it may be more meaningful to determine the unbound LTG concentration in plasma than the total concentration.Unbound LTG in plasma was extracted by ultrafiltration. High-performance liquid chromatography (HPLC) was used to measure unbound LTG concentration. This method was validated by studies of its selectivity, linearity, lower limit of quantification (LLOQ), accuracy, precision, recovery, and stability.The method was validated over a linear range of 0.2 to 10.0 μg·mL^–1, and its LLOQ was 0.2 μg·mL^–1. The method’s relative standard deviations (RSDs) for intra-day and inter-day precision were less than 15%, and its accuracy (RE) was ±4.69%. The recoveries of unbound LTG at three different concentrations satisfied the requirements for the analysis of biological samples, and no significant degradation of LTG was observed under different storage conditions.A simple HPLC method showed good performance when used to measure unbound LTG concentration. This method might be used to study the relationship between unboundLTG concentrations and its effectiveness according to TDM.     

基于UPLC-MS/MS技术的人血清中利培酮及其代谢产物的治疗药物监测

目的建立一种快速测定人血清中利培酮及其代谢产物9-羟基利培酮浓度的超高效液相色谱串联质谱法(UPLC-MS/MS)。方法以利培酮-d4为内标,以Waters Acquity UPLC BEH C18(2.1×50 mm,1.7μm)为色谱柱,柱温:50℃,0.1%甲酸水溶液(A)~0.1%甲酸甲醇(B)为流动相,快速进行治疗药物监测。结果在1~100 ng/ml,利培酮和9-羟基利培酮的线性良好(r>0.999),低、中、高质控的日内和日间精密度的RSD均小于6.0%,基质效应在92.4%~106.7%,RSD小于6.5%。结论本方法操作简单,灵敏度高、准确度好,可在4 min中完成一次标本检测,通量高,可满足临床对利培酮和9-羟基利培酮检测的需求。     

Paliperidone: new drug. Just a metabolite of risperidone, a neuroleptic soon off-patent

(1) For patients with schizophrenia, risperidone is one of many available neuroleptics. It has no tangible advantages over conventional neuroleptics such as haloperidol. (2) Paliperidone, the main active metabolite of risperidone, has now arrived on the European market, in the form of sustained-release osmotic tablets. Clinical evaluation is based on 3 placebo-controlled trials lasting 6 weeks. As expected, paliperidone was effective in relieving symptoms of schizophrenia. However, it was no more effective than olanzapine and has not been compared with risperidone. (3) The adverse effect profile of paliperidone in these trials was predictable, consisting mainly of short-term neurological effects and dose-dependent weight gain. Paliperidone also provokes tachycardia and lengthens the QT interval in some patients. The rigid osmotic tablets can cause gastrointestinal complications. (4) Paliperidone does not represent a therapeutic advance. It is better to continue using a conventional neuroleptic such as haloperidol.     

A rapid HPLC method for plasma and serum mexiletine determination and its use in therapeutic drug monitoring

A HPLC method for the determination of mexiletine in human plasma and serum is described. Serum or plasma after addition of mexiletine and internal standard was extracted with diisopropyl ether. The extract was then evaporated and dissolved in the mobile phase. An aliquot of the solution was chromatographed on a reversed-phase C8 column. The peaks were detected by UV (214 nm) at room temperature. The limit of detection of mexiletine was approximately 0.02 mg/l of plasma or serum. The validity of the method is discussed and compared with other methods.     

Therapeutic drug monitoring in methadone maintenance: choosing a matrix

Methadone maintenance is the premier pharmacological treatment for opioid addiction, but it is rarely informed by evidence-based practice guidelines for dosage monitoring and adjustment. Such guidelines are crucial because the pharmacokinetics of methadone vary greatly among patients, and this variation may account for differences in treatment outcome. We review the pharmacokinetics of methadone and factors that may alter it (including drug interactions, disease states, and idiosyncratic differences among patients). Also reviewed are prospects for therapeutic drug monitoring (TDM) of methadone in plasma, urine, sweat, and saliva. Due to its ease of collection and its presumed representation of the bioavailable free-fraction of methadone, saliva may be a promising matrix. However, saliva methadone concentrations are influenced by salivary pH, and future studies are needed to determine how to control for that. Administrative, medical, and social implications of methadone TDM are briefly discussed.     

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.     

Therapeutic drug monitoring of mirtazapine, desmethylmirtazapine, 8-hydroxymirtazapine, and mirtazapine-N-oxide by enantioselective HPLC with fluorescence detection

The tetracyclic antidepressant mirtazapine has been in clinical use for several years as a racemic drug. Because of a relatively narrow therapeutic index, therapeutic drug monitoring may be helpful to individually optimize therapy with mirtazapine. An enantioselective high-performance liquid chromatography (HPLC) method with fluorescence detection has been developed for the quantification of mirtazapine, desmethyl mirtazapine, 8-hydroxy mirtazapine, and mirtazapine N-oxide. The method is suitable for the analysis of plasma and urine samples in the range from 1 to 100 ng/mL with precision (coefficient of variation, or CV) between 12% and 19%. The sample preparation step comprises a liquid-solid extraction procedure with good recoveries, between 85% and 99%. Patient samples for therapeutic drug monitoring as well as concentration-time series were assayed and the resulting enantiomer ratios analyzed. Typical trough levels were between 1 and 100 ng/mL, with enantiomer ratios of approximately 0.42 (S/R). In concentration-time series, enantiomer ratios distinctively greater than 1 were observed at early time points. Because the enantiomers of mirtazapine and desmethyl mirtazapine have different pharmacological properties, the method is believed to be helpful in understanding the concentration-effect relationships in the former.     

Therapeutic drug monitoring of tacrolimus with the dried blood spot method

In a preliminary investigation an assay for tacrolimus based on fingerprick sampling and consecutive application as a blood spot on sampling paper has been developed. The dried blood spot was analysed by HPLC-tandem mass spectrometry. The validated range was 1-30 microg/l. Intra- and inter-assay variability for precision and accuracy was <7.5% and 15%, respectively. Tacrolimus concentrations of 24 stable out patients were compared after both blood spot sampling and conventional venous sampling. Method agreement was investigated with the methods of Passing and Bablok and Bland Altman and proved suitable for clinical use. The dried blood spot method for tacrolimus seems promising for patient monitoring.     

Therapeutic drug monitoring of nelfinavir in pregnancy: a case report

One of the indications for therapeutic drug monitoring (TDM) may be the use of antiretroviral agents during pregnancy. We report on a case in which repeated low plasma levels of nelfinavir were observed. After an initial good virologic response, virologic failure appeared to occur, and dose modifications guided by TDM were performed. Although a causal relationship cannot be proven, viral load became undetectable after our interventions. A healthy uninfected daughter was born.     

Therapeutic drug monitoring of mirtazapine and its metabolite desmethylmirtazapine by HPLC with fluorescence detection

A selective and sensitive HPLC method is described for therapeutic drug monitoring of the antidepressant drug mirtazapine and its active metabolite desmethylmirtazapine. Liquid/solid extraction with C18 cartridges was used for cleanup of plasma samples. The chromatographic separation was carried out on a phenylhexyl column. No interference from other coadministered antidepressants has been observed in 234 samples from 184 patients. The calibration range used was from 1 ng/mL to 100 ng/mL. The analytic method has proven robust and well suited for therapeutic drug monitoring. In addition to qualitative and quantitative validation data for the assay method, concentration measurements in samples from patients on mirtazapine therapy and the relevant dosing information are presented. Median drug levels after a 15-mg dose were 37 ng/mL mirtazapine and 20 ng/mL desmethylmirtazapine. When a 60-mg dose was administered, median concentrations of 83 ng/mL mirtazapine and 65 ng/mL desmethylmirtazapine were found.     

Preclinical factors affecting the interindividual variability in the clearance of the investigational anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid

Cancer chemotherapy is characterized by significant interindividual variations in systemic clearance, therapeutic response, and toxicity. These variations are due mainly to genetic factors, leading to alterations in drug metabolism and/or target proteins. The aim of this study was to determine, using a human liver bank (N=14), the interindividual variations in the expression and activity of liver enzymes that metabolize the investigational anticancer drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA), i.e cytochrome P450 (CYP1A2) and uridine diphosphate glucuronosyltransferase (UGT1A9/2B7). In addition, interindividual variations in enzyme inhibition, hydrolysis of DMXAA acyl glucuronide (DMXAA-G) by plasma and hepatic microsomes, and the binding of DMXAA by plasma proteins also were examined. The results indicated that there was approximately one order of magnitude of interindividual variation in the expression of CYP1A2 and UGT2B7, activity of the enzymes toward DMXAA, and inhibition potency (IC(50)) by diclofenac, cyproheptadine, and alpha-naphthoflavone. The enzyme activities toward DMXAA and IC(50) values were closely correlated with enzyme expression. There was a smaller (2- to 3-fold) variation in the enzyme-catalyzed hydrolysis of DMXAA acyl glucuronide in human plasma and liver microsomes (N=6) and in the binding of DMXAA by plasma proteins in humans. In conclusion, the interindividual variability of DMXAA disposition observed in vitro might reflect the greater elimination variability (>one order of magnitude) in Phase I cancer patients. The variability in DMXAA clearance in these cancer patients would be due mainly to differences in its metabolism and its metabolic inhibition by co-administered drugs. To a lesser extent, variability in the clearance of DMXAA could be due to the hydrolysis of its acyl glucuronide and/or its binding to plasma proteins. Further study is needed to examine the genotype-phenotype relationship, and the result, together with therapeutic drug monitoring may provide a useful strategy for optimizing DMXAA treatment.