Drug Monitoring In Clinical Practice Research Articles

A Rapid and Simple HPLC-MS/MS Method for the Quantitative Determination of Colistin for Therapeutic Drug Monitoring in Clinical Practice.

Colistin is the last-line option for the treatment of multidrug-resistant gram-negative bacterial infections with narrow therapeutic window. It is essential to ensure its efficacy and safety by therapeutic drug monitoring (TDM). Quantitative determination of colistin is difficult due to its complex ingredients. Previous determination methods demand intricate sample pre-treatment which are not only time-consuming but also costly, and is difficult to apply in clinical practice. Therefore, in order to carry out quantitative determination of colistin accurately and quickly, we establish a rapid high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) with simple sample pre-treatment process. The sample was purified by acetonitrile to remove the plasma protein. Then purified colistin was effectively separated from terfenadine, an internal standard (IS) using Phenomenex Kinetex C18 column (50.0×2.1mm, 5µm) with acetonitrile and water mobile phase at a flow rate of 0.5 mL/min and 40°C column temperature. Colistin and IS were monitored in positive ion mode. Our method expressed good linearity in 50.0~6000 ng/mL of colistin B and 28.31~3397.51 ng/mL of colistin A in plasma. Methodology validations, including selectivity, precision, accuracy, recovery, stability, matrix effect, and dilution integrity met acceptance criteria of Bioanalytical Method Validation (M10) of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).

The effect of therapeutic drug monitoring of risperidone and aripiprazole on weight gain in children and adolescents: the SPACe 2: STAR (trial) protocol of an international multicentre randomised controlled trial

BackgroundAntipsychotic drugs are an important part of the treatment of irritability and aggression in children with an autism spectrum disorder (ASD). However, significant weight gain and metabolic disturbances are clinically relevant side effects of antipsychotic use in children. In the SPACe study, we showed positive correlations between both risperidone and aripiprazole plasma trough concentrations and weight gain over a 6-month period. The trial SPACe 2: STAR is designed as a follow-up study, in which we aim to research whether therapeutic drug monitoring in clinical practice can prevent severe weight gain, while retaining clinical effectiveness.MethodsSPACe 2: STAR is an international, multicentre, randomised controlled trial (RCT). One hundred forty children aged 6 to 18 who are about to start risperidone or aripiprazole treatment for ASD related behavioural problems will be randomised into one of two groups: a therapeutic drug monitoring (TDM) group, and a care as usual (CAU) group. Participants will be assessed at baseline and 4, 10, 24, and 52 weeks follow-up. In the TDM group, physicians will receive dosing advice based on plasma levels of risperidone and aripiprazole and its metabolites at 4 and 10 weeks. Plasma levels will be measured in dried blood spots (DBS). The primary outcome will be BMI z-score at 24 weeks after start of antipsychotic treatment. Among the secondary outcomes are effectiveness, metabolic laboratory measurements, levels of prolactin, leptin and ghrelin, extrapyramidal side effects, and quality of life.DiscussionThis will be the first RCT evaluating the effect of TDM of antipsychotic drugs in children and adolescents. Thus, findings from SPACe 2: STAR will be of great value in optimising treatment in this vulnerable population.Trial registrationClinicalTrials.gov Identifier: NCT05146245. EudraCT number: 2020–005450-18. Sponsor protocol name: SPACe2STAR. Registered 8 June 2021. Protocol Version 6, Protocol date: 18 august 2022.

Best Practices to Implement Dried Blood Spot Sampling for Therapeutic Drug Monitoring in Clinical Practice.

Background:Sampling of blood at home to determine the concentration of drugs or other compounds can be effective in limiting hospital-based sampling. This could lower hospital visits and patient burden, improve the quality of life, and reduce health care costs. Dried blood spot (DBS) microsampling is often used for this purpose, wherein capillary blood, obtained by pricking the heel or finger, is used to measure different analytes. Although DBS has several advantages over venous blood sampling, it is not routinely implemented in clinical practice. To facilitate the bench to bedside transition, it is important to be aware of certain challenges that need to be considered and addressed.Results:Here, important considerations regarding the implementation of DBS in clinical practice, the choice of patients, blood sampling, transport, and laboratory analysis are discussed. In addition, we share our experience and provide suggestions on how to deal with these problems in a clinical setting.

Pharmacokinetic and pharmacodynamic analysis of cefoperazone/sulbactam for the treatment of pediatric sepsis by Monte Carlo simulation.

Pediatric sepsis syndrome is one of the most common reasons for pediatric intensive care unit hospitalization (PICU). Cefoperazone/sulbactam is a time-dependent beta-lactamase inhibitor combination which has been widely used in the treatment of sepsis. But the pharmacokinetic (PK) and pharmacodynamic (PD) data of cefoperazone/sulbactam are unknown in children with sepsis. The present work aimed to determine whether the usual dosing regimens of cefoperazone/sulbactam (1 hour infusion, 50 mg kg-1, every 12 hours) were suitable for these patients in PICU. A total of fourteen patients were enrolled and the PK parameters were estimated by non-compartmental analysis using WinNonlin software. The t1/2 and AUC0-12 of cefoperazone and sulbactam were 3.60 and 1.77 h, and 900.97 and 67.68 h μg mL-1, respectively. The Vd and CL of cefoperazone and sulbactam were 1.65 L and 5.16 L, and 17.41 mL min-1 and 122.62 mL min-1, respectively. The probability of target attainments (PTAs) of cefoperazone at different minimum inhibitory concentrations (MICs) based on the percentage time that concentrations exceed the minimum inhibitory concentration (% T > MIC) value were performed by Monte Carlo simulation and PTA was >90% at MICs ≤16 μg mL-1. The PK/PD profile of dosing regimens tested will assist in selecting the appropriate cefoperazone/sulbactam regimens for these patients. At a target of 80% T > MIC, the usual dosing regimens can provide good coverage for pathogens with MICs of ≤32 μg mL-1. The ratio between cefoperazone and sulbactam at 1 : 1 may be more suitable in pediatric sepsis. Individual dose and therapeutic drug monitoring in clinical practice will help achieve the best therapeutic effect while minimizing toxicity.

Relation between plasma concentration of Risperidone and its efficacy in patients with schizophrenia: A review article

Aim of the work: To determine the relation between Risperidone plasma concentration and its efficacy in patients with schizophrenia to assess the value of therapeutic drug monitoring in clinical practice. Method: In February 2020, a search was conducted in the period from 2000 to 2020 using Google scholar, Pubmed and Science Direct as search engine. The key words used in this search were Risperidone, plasma concentration, schizophrenia. Articles were selected for inclusion in this search if they involved a test for the correlation between plasma concentration and efficacy. Results: Limited number of studies was found. Among 14 studies, 10 yielded no correlation between Risperidone plasma levels and its efficacy while 4 studies showed positive results. To investigate the relation between Risperidone plasma concentration and clinical response, the most common tools used are HPLC for determination of plasma concentration and PANSS for assessment of clinical response. Conclusion: The majority of studies showed no correlation and therapeutic drug monitoring of Risperidone is still unclear. Further research is needed in this area.

Meropenem use and therapeutic drug monitoring in clinical practice: a literature review.

Meropenem, a carbapenem antibiotic, is widely prescribed for the treatment of life-threatening infections. The main parameter associated with its therapeutic success is the percentage of time that the levels remain above the minimum inhibitory concentration. Inadequate levels of meropenem can lead to therapeutic failure and increase the possibility of microbial resistance. The employment of strategies involving dose regimens and drug pharmacodynamics has become increasingly important to optimize therapies. In the present study, we conducted a review with the purpose of assembling information about the clinical use of meropenem and therapeutic drug monitoring. A literature review emphasizing the application of therapeutic drug monitoring (TDM) of meropenem in clinical practice has been done. To identify articles related to the topic, we performed a standardized search from January 21, 2020 to December 21, 2020, using specific descriptors in PubMed, Lilacs and Embase. In total, 35 studies were included in the review. The daily dose of meropenem commonly ranged from 3 to 6g/day. Critically ill patients and those with impaired renal function appear to be the most suitable patients for the application of meropenem TDM, in order to guide therapy. We observed that most of the studies recommend TDM and that, in nine locations, the TDM of meropenem and of other beta-lactams is a routine practice. TDM data can help to maximize the clinical outcomes of the treatment with meropenem. It can also improve the patient care by providing suitable levels of meropenem, guiding the most appropriate dose regimens, which is the main parameter associated with therapeutic success. The findings from this review suggest that the therapeutic monitoring of meropenem can be beneficial, since it adjusts the treatment and aids clinical outcomes. It does so by indicating the appropriate dosage and preventing failure, toxicity and possible antimicrobial resistance. The multidisciplinary effort, basic knowledge and communication among the medical team are also essential.

Construction of Quantitative Analysis Workflow for Determination of Serum Concentrations of Monoclonal Antibody Drugs Aiming to Promote Therapeutic Drug Monitoring in Clinical Practice

Construction of Quantitative Analysis Workflow for Determination of Serum Concentrations of Monoclonal Antibody Drugs Aiming to Promote Therapeutic Drug Monitoring in Clinical Practice

Interlaboratory analysis of teicoplanin plasma concentration assays among Chinese laboratories.

Teicoplanin is widely used for the treatment of infections caused by drug-resistant Gram-positive bacteria. Since there is a good correlation between trough levels and clinical outcome, therapeutic drug monitoring (TDM) is recommended to achieve better clinical curative effects. However, TDM of teicoplanin is not routine in China. So, a programme was initiated in 2017, including both HPLC method establishment and interlaboratory quality assessment, for the measurement of teicoplanin. A main centre and a quality control centre were set up in the study. An HPLC-based method of teicoplanin determination in plasma was developed by the main centre. Analysis was performed using a Waters Symmetry C18 column (250mm×4.6mm, 5µm). The mobile phase was NaH2 PO4 (0.01mol/L) and acetonitrile (75:25 v/v; pH 3.3), with a flow rate of 1.0mL/min and a detection wavelength of 215nm. Piperacillin sodium was selected as an internal standard (IS). Twenty-six additional TDM centres were then recruited to adopt this method. Then, all the centres were asked to take part in a quality control assessment evaluated by the quality control centre. For all TDM centres, linearity of teicoplanin concentration ranges was between 3.125 and 100µg/mL. Intraday and interday accuracies ranged from 87.1% to 118.4%. Intraday and interday precision ranged from 0.3% to 13.8%. Therapeutic drug monitoring centres all passed inter-room quality assessment. All samples tested met the acceptance criteria. Then, 542 samples were collected. Patients with sub-optimal (≤10mg/L) plasma teicoplanin concentrations constituted 42% of the total study population. For the first time, a simple, rapid and accurate HPLC method for determining teicoplanin levels was successfully applied to therapeutic drug monitoring in clinical practice for twenty-seven TDM centres in China. The results demonstrated excellent interlaboratory agreement for teicoplanin testing and provide support for clinical laboratory quality management and results inter-accreditation.

Posaconazole therapeutic drug monitoring in clinical practice and longitudinal analysis of the effect of routine laboratory measurements on posaconazole concentrations.

SummaryPosaconazole is indicated for prophylaxis and treatment of invasive aspergillosis. Therapeutic drug monitoring (TDM) of posaconazole is used to optimise drug exposure. The aim of this study was to analyse and describe the TDM practices and exposure of posaconazole tablets. Patients who received posaconazole for treatment or prophylaxis of fungal infections were included in the study. The following therapeutic window was defined: if concentration was low (<0.7 mg/L for prophylaxis or < 1.5 mg/L for treatment) or high (>3.75 mg/L), the hospital pharmacist provided the physician with dosage advice, which implementation to patient care was analysed. A longitudinal analysis was performed to analyse if different confounding variables had an effect on posaconazole concentrations. Forty‐seven patients were enrolled resulting in 217 posaconazole trough concentrations. A median of 3 (IQR 1‐7) samples was measured per patient. The median concentration was 1.7 mg/L (IQR 0.8‐2.7) for prophylaxis and 1.76 mg/L (IQR 1.3‐2.3) for treatment. Overall, 78 posaconazole concentrations were out of the therapeutic window. For 45 (54%) of these concentrations, a dosage change was recommended. In the longitudinal analysis, the laboratory markers and patient baseline variables did not have an effect on posaconazole concentrations. Adequate posaconazole exposure was shown in 64% (affected 28 patients) of the measured concentrations. TDM practice of posaconazole can be improved by increasing the implementation rate of dose recommendation by a multidisciplinary antifungal stewardship team.

Therapeutic drug monitoring of tumour necrosis factor inhibitors in the management of chronic inflammatory diseases.

Tumour necrosis factor inhibitor therapy has drastically changed the management of chronic inflammatory diseases. Some important drawbacks that can cause loss of response during treatment with these drugs are related to their large individual variability, the disease burden and the formation of antidrug antibodies that increase its clearance. Therapeutic drug monitoring of these drugs is not yet recommended by all scientific societies, and if so, only in patients with inflammatory symptoms. Proactive therapeutic drug monitoring represents a new strategy with many potential clinical benefits, including the prevention of immunogenicity, a reduction in the need for rescue therapy and greater durability of tumour necrosis factor inhibitor treatment. The review is based on a systematic search of the literature for controlled trials, systematic reviews, experimental studies, guideline papers and cohort studies addressing the best practice in tumour necrosis factor inhibitor therapeutic drug monitoring. Although there is ample evidence supporting the use of therapeutic drug monitoring in clinical practice to achieve better outcomes, some challenges have been detected. Many studies are focused on finding solutions for the lack of standardization of analytical methods to measure tumour necrosis factor inhibitor and antidrug antibodies concentrations. Other challenges are development of effective cost-saving proactive algorithms to identify optimal drug concentrations and the research on the role of antidrug antibodies, especially in the management and prevention of loss of response. Therapeutic drug monitoring of tumour necrosis factor inhibitor offers a rational approach to the optimization of the treatment of chronic inflammatory disease. Although prospective controlled trials yield little conclusive evidence of its benefits, there is growing acceptance of its value in clinical practice.

Population pharmacokinetics of Rilpivirine in HIV-1-infected patients treated with the single-tablet regimen rilpivirine/tenofovir/emtricitabine.

Rilpivirine, prescribed for the treatment of HIV infection, presents an important inter-individual pharmacokinetic variability. We aimed to determine population pharmacokinetic parameters of rilpivirine in adult HIV-infected patients and quantify their inter-individual variability. We conducted a multicenter, retrospective, and observational study in patients treated with the once-daily rilpivirine/tenofovir disoproxil fumarate/emtricitabine regimen. As part of routine therapeutic drug monitoring, rilpivirine concentrations were measured by UPLC-MS/MS. Population pharmacokinetic analysis was performed using NONMEM software. Once the compartmental and random effects models were selected, covariates were tested to explain the inter-individual variability in pharmacokinetic parameters. The final model qualification was performed by both statistical and graphical methods. We included 379 patients, resulting in the analysis of 779 rilpivirine plasma concentrations. Of the observed trough individual plasma concentrations, 24.4% were below the 50ng/ml minimal effective concentration. A one-compartment model with first-order absorption best described the data. The estimated fixed effect for plasma apparent clearance and distribution volume were 9L/h and 321L, respectively, resulting in a half-life of 25.2h. The common inter-individual variability for both parameters was 34.1% at both the first and the second occasions. The inter-individual variability of clearance was 30.3%. Our results showed a terminal half-life lower than reported and a high proportion of patients with suboptimal rilpivirine concentrations, which highlights the interest of using therapeutic drug monitoring in clinical practice. The population analysis performed with data from "real-life" conditions resulted in reliable post hoc estimates of pharmacokinetic parameters, suitable for individualization of dosing regimen.

Development and Validation of a Simultaneous Quantification Method of 14 Tyrosine Kinase Inhibitors in Human Plasma Using LC-MS/MS.

A sensitive liquid chromatography coupled with tandem mass spectrometry (MS/MS) method for the analysis in a small volume of plasma of 14 tyrosine kinase inhibitors currently used (imatinib, dasatinib, ibrutinib, ponatinib, trametinib, sunitinib, cobimetinib, dabrafenib, erlotinib, lapatinib, nilotinib, bosutinib, sorafenib, and vemurafenib) has been developed and validated. This multianalyte liquid chromatography coupled with MS/MS assay is of interest for anticancer drug combination therapy. After a simple protein precipitation of plasma samples, the chromatographic separation was performed using an ultra performance liquid chromatography system coupled with MS/MS in a positive ionization mode. The mobile phase consisted of a gradient elution of 10 mmol/L formate ammonium buffer containing 0.1% (vol/vol) formic acid (phase A) and acetonitrile with 0.1% (vol/vol) formic acid (phase B) at a flow rate of 300 μL/min. The analysis time was 5.0 minutes per run, and all analytes and internal standard eluted within 1.45-1.79 minutes. The calibration curves were linear over the range from 1 to 500 ng/mL for bosutinib, cobimetinib, dasatinib, ibrutinib, and trametinib, from 5 to 500 ng/mL for ponatinib and sunitinib; from 50 to 2500 ng/mL for lapatinib; from 750 to 100,000 ng/mL for vemurafenib, and from 10 to 2500 ng/mL for dabrafenib, erlotinib, imatinib, nilotinib, and sorafenib, with coefficients of correlation above 0.99 for all analytes. The intra- and interday imprecisions were below 14.36%. This method was successfully applied to therapeutic drug monitoring in clinical practice.

A Systematic Literature Review Approach to Estimate the Therapeutic Index of Selected Immunosuppressant Drugs After Renal Transplantation.

Drugs that exhibit close margins between therapeutic and toxic blood concentrations are considered to have a narrow therapeutic index (NTI). The Food and Drug Administration has proposed that NTI drugs should have more stringent bioequivalence standards for approval of generic formulations. However, many immunosuppressant drugs do not have a well-defined therapeutic index (TI). We sought to determine whether safety, efficacy, and pharmacokinetic data obtained from the medical literature through a comprehensive literature search could be used to estimate the TI of cyclosporine, tacrolimus, and sirolimus. In this analysis, we considered TI ≤2 as a criterion to define a drug as having an NTI. Published literature indicates that cyclosporine has a TI of 2-3, which falls just short of our criteria to be classified as having an NTI. We found sirolimus and tacrolimus to have a therapeutic range of 5-12 ng/mL and of 5-20 ng/mL, respectively, but were unable to calculate the TI. Although the current literature does not provide a clear indication that these drugs have an NTI, the routine use of therapeutic drug monitoring in clinical practice suggests that more stringent testing of their pharmacokinetic and pharmacodynamic properties should be performed before the approval of generic formulations.

A microcosting study of immunogenicity and tumour necrosis factor alpha inhibitor drug level tests for therapeutic drug monitoring in clinical practice.

Objectives. To identify and quantify resource required and associated costs for implementing TNF-α inhibitor (TNFi) drug level and anti-drug antibody (ADAb) tests in UK rheumatology practice. Methods. A microcosting study, assuming the UK National Health Service perspective, identified the direct medical costs associated with providing TNFi drug level and ADAb testing in clinical practice. Resource use and costs per patient were identified via four stages: identification of a patient pathway with resource implications; estimation of the resources required; identification of the cost per unit of resource (2015 prices); and calculation of the total costs per patient. Univariate and multiway sensitivity analyses were performed using the variation in resource use and unit costs.Results. Total costs for TNFi drug level and concurrent ADAb testing, assessed using ELISAs on trough serum levels, were £152.52/patient (range: £147.68–159.24) if 40 patient samples were tested simultaneously. For the base–case analysis, the pre-testing phase incurred the highest costs, which included booking an additional appointment to acquire trough blood samples. The additional appointment was the key driver of costs per patient (67% of the total cost), and labour accounted for 10% and consumables 23% of the total costs. Performing ELISAs once per patient (rather than in duplicate) reduced the total costs to £133.78/patient.Conclusion. This microcosting study is the first assessing the cost of TNFi drug level and ADAb testing. The results could be used in subsequent cost-effectiveness analyses of TNFi pharmacological tests to target treatments and inform future policy recommendations.

Therapeutic drug monitoring in a developing nation: a clinical guide.

Therapeutic drug monitoring is aimed at using drug concentration measurements to manage a patient’s medication requirement and optimise clinical outcome, particularly in respect of drugs with narrow therapeutic index. Typically, immunoassay methods of various techniques are employed with the advantage of rapid turnaround time and ease of operation. The chromatographic methods are specific and cost effective, though more demanding and require technical expertise. The most crucial aspect of any therapeutic drug monitoring service is the expert clinical interpretation of drug concentration measurements taking into consideration individual pharmacokinetic variability in drug disposition across different populations. The setting up of a therapeutic drug monitoring service requires enormous resources, both in terms of equipment and trained personnel. This poses considerable constraints in developing countries due to limited scarce resources, coupled with ignorance among health practitioners on the relevance of therapeutic drug monitoring in clinical practice. Consequently, the need for advocacy, training and encouragement of health practitioners on the usefulness of therapeutic drug monitoring in enhancing patient care and overall clinical outcome in a developing country such as Nigeria can never be over-emphasised.

THU0186 Infliximab VS Etanercept: the Importance of Immunogenicity and Serum Drug Monitoring in Clinical Practice

BackgroundTreatment with tumor necrosis factor (TNF) inhibitors in rheumatoid arthritis (RA) patients is based on the principle 'one size fits all', but different immunogenicity of these drugs has a profound...

Infliximab Therapeutic Drug Monitoring in Clinical Practice: Indications and Utility

Purpose: Infliximab (IFX) is effective for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). Measurement of serum IFX levels and antibodies to infliximab (ATI) have shown utility in the management of inflammatory bowel disease (IBD) patients with inadequate/loss of response (LOR) to IFX or infusion reactions. Evolving evidence suggests additional indications for therapeutic drug monitoring using IFX and ATI concentrations in patients without specific response-related issues, and in patients restarting IFX after drug holiday, may help predict and optimize response to IFX. Here, we report the spectrum of use of IFX and ATI testing at an academic IBD Center, including novel indications such as reintroduction of IFX and therapeutic drug monitoring. Methods: We conducted a retrospective review of the electronic medical records of all IBD patients at our institution who underwent IFX/ATI testing between January 1, 2010 and December 31, 2012. The testing date, results, indication for testing, and clinical management based on test results were obtained. Results: One hundred forty two IBD patients (83 with CD, 58 with UC, one with indeterminate colitis) underwent 205 IFX/ATI tests. Sixty-one percent (87/142) of patients received concomitant immunosuppression (IS). The most common indications for testing were inadequate/LOR (50%) and therapeutic drug monitoring (19%). Of 49 patients with confirmed LOR, 50% (25/49) had non-therapeutic IFX levels, and additional 16% (8/49) had detectable ATI with undetectable IFX levels. Thirty-eight patients underwent testing for therapeutic drug monitoring: 16% (6/38) had nontherapeutic IFX levels, 3% (1/38) had detectable ATI, and 3% (1/38) had measurable IFX with detectable ATI. Of seven patients tested prior to reintroduction of IFX, 43% (3/7) were found to have detectable ATI. Of 11 patients tested after re-challenge with IFX, 55% (6/11) had nontherapeutic IFX concentrations, and 36% (4/11) had detectable ATI. Concomitant IS therapy was significantly associated with negative ATI status (p=0.0026). Non-therapeutic IFX concentration was associated with higher C-reactive protein (p<0.0001). Testing resulted in changes in therapy in 67% of patients with LOR, and 21% of patients undergoing routine therapeutic drug monitoring. Conclusion: The measurement of IFX and ATI concentrations in IBD patients receiving IFX can aid decision-making in multiple clinical scenarios and frequently results in changes in clinical care. Disclosure - Dr. Sandborn - Consultant and Grant/Research Support: Janssen Biotech, Inc, Consultant: P rometheus Laboratories, Inc.; Dr. Levesque - Consultant: Prometheus Laboratories, Inc.

Role of anticonvulsant therapeutic drug monitoring in improving clinical outcomes: An example of 12 adult epilepsy patients

1 , Jasmina Milovanovic 2 , Snežana V Jankovic 2 , Natalija Todorovic 3 , Nemanja Rancic 4 , Nikola Jestrovic 5 , 6 , Slobodan Jankovic 2 , Mihajlo Jakovljevic 2 1 Centar za radiolosku dijagnostiku , Klinicki centar Kragujevac, Srbija 2 Odsek za farmakologiju I toksikologiju, Fakultet medicinskih nauka, Kragujevac, Srbija 3 Klinika za neurologiju, Klinicki centar Kragujevac, Srbija 4 Fakultet medicinskih nauka, Univerzitet u Kreagujevcu, Srbija 5 Merck Sharp & Dohme Idea Inc., AG Beograd, Srbija 6 Farmaceutski fakultet, Univerzitet u Ljubljani, Slovenija Epilepsy, one of the most common neurological dis- eases, demands persistent and long-term therapy. In spite of the available therapeutic interventions for seizure dis- orders, the incidence of epilepsy and mortality associated with status epilepticus remain significant (1). The goal of seizure management is satisfying seizure control with minimal side effects (2). Quality of life (QoL) studies have suggested that patients who suffer even single seizure per year exhibit significantly reduced QoL (3). Among the wide range of medications offered in the market, valproic acid is still considered by many to be a gold standard to treat many convulsive disorders, including absence , gen- eralised tonic-clonic seizures, myoclonic juvenile seizures, and photosensitive seizures . It also exhibits an acceptable toxicity profile compared with other anticonvulsants (4). The Serbian health care system is still not capable of sys- temic therapeutic drug monitoring in clinical practice. The underlying reasons are typical for an upper-middle income transitional market and are attributed to both financial con- straints and the lack of skilled, highly educated human re- source availability in the field. These reasons influenced the authors to report pilot trial results to provide small move forward on the issue among local clinicians (5). The core aim of the trial presented was an exploration of the dose-response relationship in small group of twelve adults suffering from epilepsy. The authors studied fre- quencies of drug adverse effects associated with long-term monotherapy and evaluated the appropriateness and clini- cal value of regular therapeutic drug monitoring (TDM) of valproic acid. The presence of correlation between drug plasma concentration as an independent variable and fre- quency of seizures, frequency of adverse events and over- all life quality as dependent variables was also tested. The reported results are an unpublished fragment originating from large-scale collaborative project on pharmacoki- netic modelling in juvenile epilepsy treatment (3-6).

Therapeutic Drug Monitoring of Biologics for Inflammatory Bowel Disease

Although tumor necrosis factor (TNF) antagonists are effective for the treatment of Crohn's disease and ulcerative colitis, lack and loss of clinical response is a clinical challenge. Accordingly, the use of therapeutic drug monitoring has been proposed as a means to optimize treatment. This article reviews the mechanisms of and factors which influence clearance of biologics, the relationship between serum drug concentrations and antidrug antibody presence and treatment efficacy, and identifies areas for future research needs regarding the use of therapeutic drug monitoring in clinical practice. Publications regarding these topics were identified from literature searching and supplemented by review of gastroenterology meeting presentations and reference lists. The clearance of monoclonal antibodies and pegylated antibody fragments is complex, and may be affected by demographic variables, concomitant medications, inflammatory burden, and immunogenicity, leading to high interpatient variability in plasma concentration of drug and clinical response. Several observational studies have demonstrated a relationship between anti-TNF agent serum drug concentrations and/or antidrug antibody presence and various symptomatic and objective clinical endpoints. However, these relationships are not absolute, and although some algorithms for the use of therapeutic drug monitoring in clinical practice have been proposed, none have yet been validated in a prospective clinical trial. Further research to identify the most appropriate use of therapeutic drug monitoring is needed.

免疫抑制薬の TDM を基盤とした薬物治療管理のためのエビデンスの構築

免疫抑制薬の TDM を基盤とした薬物治療管理のためのエビデンスの構築