Therapeutic Drug Monitoring In Patients Research Articles

Micro/nanofluidic device for tamsulosin therapeutic drug monitoring in patients with benign prostatic hyperplasia at point of care.

Discovering the balance between toxicity and efficacy for many drugs requires therapeutic drug monitoring (TDM) of their concentrations in the blood. Here, a hot-embossed microfluidic device with a new design integrated to a nanofracture is presented for purification of blood samples from numerous proteins and cells, allowing to the separation of small molecules from blood matrix. The device was used to separate and quantitatively detect tamsulosin drug after derivatization with fluorescamine reagent, allowing converting it from a neutral molecule into a charged fluorescent complex under the experimental conditions, and thus its separation by electrophoresis. The device is portable and easy operated, and the presented method showed good linearity (R2 = 0.9948) over a concentration range of 0.1-1μg/mL. The relative standard deviation (RSD%) was below 10% (n = 3), indicating good precisions, and the limit of detection (LOD) and limit of quantitation (LOQ) values were estimated to be 0.1 and 0.55μg/mL, respectively. Whole blood samples from 10 patients with benign prostatic hyperplasia (BPH) were analyzed, showing good percentage recoveries of tamsulosin in whole blood. This point-of-care (POC), low-cost method could increase the convenience of patients and doctors, make therapies safer, and make TDM available in different regions and places.

Is tumor necrosis factor-α monoclonal therapy with proactive therapeutic drug monitoring optimized for inflammatory bowel disease? Network meta-analysis.

The efficacy and safety of anti-tumor necrosis factor-α (TNF-α) monoclonal antibody therapy [adalimumab (ADA) and infliximab (IFX)] with therapeutic drug monitoring (TDM), which has been proposed for inflammatory bowel disease (IBD) patients, are still controversial. To determine the efficacy and safety of anti-TNF-α monoclonal antibody therapy with proactive TDM in patients with IBD and to determine which subtype of IBD patients is most suitable for proactive TDM interventions. As of July 2023, we searched for randomized controlled trials (RCTs) and observational studies in PubMed, Embase, and the Cochrane Library to compare anti-TNF-α monoclonal antibody therapy with proactive TDM with therapy with reactive TDM or empiric therapy. Pairwise and network meta-analyses were used to determine the IBD patient subtype that achieved clinical remission and to determine the need for surgery. This systematic review and meta-analysis yielded 13 studies after exclusion, and the baseline indicators were balanced. We found a significant increase in the number of patients who achieved clinical remission in the ADA [odds ratio (OR) = 1.416, 95% confidence interval (CI): 1.196-1.676] and RCT (OR = 1.393, 95%CI: 1.182-1.641) subgroups and a significant decrease in the number of patients who needed surgery in the proactive vs reactive (OR = 0.237, 95%CI: 0.101-0.558) and IFX + ADA (OR = 0.137, 95%CI: 0.032-0.588) subgroups, and the overall risk of adverse events was reduced (OR = 0.579, 95%CI: 0.391-0.858) according to the pairwise meta-analysis. Moreover, the network meta-analysis results suggested that patients with IBD treated with ADA (OR = 1.39, 95%CI: 1.19-1.63) were more likely to undergo TDM, especially in comparison with patients with reactive TDM (OR = 1.38, 95%CI: 1.07-1.77). Proactive TDM is more suitable for IBD patients treated with ADA and has obvious advantages over reactive TDM. We recommend proactive TDM in IBD patients who are treated with ADA.

Direct Immersion-Solid Phase Microextraction for Therapeutic Drug Monitoring of Patients with Mood Disorders.

This article discusses a new method for monitoring drug concentrations in blood samples from patients with mood disorders. The method uses solid-phase microextraction to extract analytes directly from blood samples. It has been adapted to identify the most commonly used drugs in mood disorders, including amitriptyline, citalopram, fluoxetine, paroxetine, sertraline, trazodone, duloxetine, venlafaxine, lamotrigine, quetiapine, olanzapine, and mirtazapine. The analysis is carried out using high-performance liquid chromatography coupled with mass spectroscopy. The proposed DI-SPME/LC-MS method allows for a simple and quick screening analysis while minimizing the volume of the tested sample and solvent, in line with the principles of green analytical chemistry. The method was used to analyze 38 blood samples taken from patients with mood disorders, and drug concentrations were determined and compared with therapeutic and toxic dose ranges. This allowed for better control of the course of treatment.

P353 Optimal Interval for Therapeutic Drug Monitoring in Patients with Inflammatory Bowel Disease Receiving Stable Infliximab Maintenance Treatment

Abstract Background Recent studies suggest that proactive therapeutic drug monitoring (TDM) in patients with inflammatory bowel disease (IBD) receiving infliximab (IFX) improves clinical outcomes. However, as proactive TDM may lead to increased medical costs, we aimed to determine the optimal interval for TDM during infliximab maintenance therapy in IBD patients. Methods We conducted a retrospective analysis of a prospective cohort comprising 103 patients with IBD on IFX maintenance therapy who went through proactive TDM between February 2020 and May 2023. Following dose optimization till achieving a therapeutic trough level (TL) of 3 to 10 ug/mL, we applied the Kaplan-Meier (KM) method to calculate the time to subtherapeutic IFX TL (two consecutive IFX TLs below 3 ug/mL). Results 90% of patients had a sustained therapeutic IFX TL for 10.3 months, whilst 80% had it for 14.3 months. In multivariable analysis, IFX TL at enrollment had a association with the risk of subtherapeutic IFX TL (P=0.025). Persistence rates for therapeutic IFX TL were significantly lower in patients with IFX TL from 3 to 5 µg/mL at recruitment than in those with IFX TL >5 µg/mL (P=0.017). For patients who had IFX TL between 3 to 5 µg/mL upon enrollment, the percentage of those who maintained therapeutic IFX TL was 80% after 12.0 months. The group with IFX TL greater than 5 µg/mL had a persistence rate of 90% after 12.3 months. Conclusion These results suggest that conducting annual measurement of IFX TL in patients with IBD who are on stable maintenance therapy with IFX, which may reduce the cost of proactive TDM.

Therapeutic Drug Monitoring in Patients with Systemic Lupus Erythematosus: Utility and Gaps.

Despite advances in the treatment of patients with systemic lupus erythematous (SLE), outcomes have remained suboptimal. Persistent disease activity, patient comorbidities and drug toxicities contribute to the accrual of progressive irreversible damage and high rates of morbidity and mortality. Currently, similar drug doses and regimens are promulgated in the treatment guidelines for all SLE patients, despite the vast differences in patient and environmental factors that affect the drugs' metabolism and blood concentrations. This causes a disconnect between drug dosing and drug blood concentrations, which can then result in unpredictability in drug toxicities and therapeutic effects. In this review, we discuss commonly used oral immunosuppressive medications in SLE, their pharmacogenomics, and factors affecting their metabolism and blood concentrations. Further, we highlight the role of therapeutic drug monitoring in SLE, which is the first accessible step to individualising therapy.

The development and validation of a liquid chromatography tandem mass spectrometry method for the quantification of selinexor and its application in Chinese multiple myeloma patients.

Selinexor is a nuclear exportin-1 (XPO1) inhibitor that has been approved for the treatment of multiple myeloma patients. However, sustained use of selinexor may result in some undesirable consequences. Furthermore, selinexor has moderate inter-patient variability. Herein, we developed an ultrahigh-performance liquid chromatography tandem mass spectrometry method for measuring selinexor levels in human plasma ranging from 1 to 1000 ng mL-1. Furthermore, the developed approach was validated in accordance with FDA criteria. The established approach demonstrated inter-day and intra-day precision, expressed as the relative standard deviation, of less than 8%, with accuracies of less than 6%, expressed as relative error. The results showed that the protein depletion was quite complete for selinexor extraction, with recoveries ranging from 85.89 to 108.38%. The validated method facilitates the quantitation of selinexor in multiple myeloma patients. The selinexor plasma concentration exhibits obvious inter-patient' variability after administration. Thus, it is necessary to make a personalized prescription through therapeutic drug monitoring. Furthermore, the change in platelet counts before and after selinexor treatment was shown to be related to the plasma concentration at 3 h after administration, which provides the basis for therapeutic drug monitoring sampling time points and a method for predicting the occurrence of thrombocytopenia. In conclusion, the developed method can be used for the quantification of the plasma concentration of selinexor, and it is of great significance to conduct therapeutic drug monitoring for patients taking selinexor in order to enhance therapeutic effects and prevent the occurrence of adverse reactions.

A validated LC-MS/MS method for determination of Molnupiravir and Favipiravir in human plasma; Assessment of the remarkable potential synergistic effect against SARS-CoV-2 Infection: Application to a pharmacokinetic study in healthy Egyptian volunteers

Several clinical trials were carried out to find the route for an efficient therapy against SARS-CoV-2 infection. Mono- and dual therapy of various antivirals were investigated and found to have a clinical benefit in infected patients. Some of these antivirals are Molnupiravir (MOL) and Favipiravir (FAV), both drugs were evaluated for combined antiviral activity in some recent clinical trials. In this study, an efficient, simple, and rapid LC-MS/MS method for simultaneous determination of N-hydroxycytidine (NHC), MOL active metabolite, and FAV in human plasma of healthy volunteers was developed. Plasma protein precipitation was performed using acetonitrile. Compounds’ separation was achieved using Agilent Zorbax Eclipse plus C18, 4.6 × 150 mm, 3.5 µm and an isocratic elution of a mobile phase composed of methanol − 0.2 % acetic acid (10:90, v/v) at a flow rate of 0.5 mL/min using pyrazinamide as an internal standard (IS). Drugs were quantified using API 6500 + Qtrap mass spectrometer employing a selective ion mode combining a positive and negative ESI interface. The bioanalytical method was validated in accordance with the US-FDA bioanalytical guidance. The calibration range for both NHC and FAV was 10.0–––10000.0 ng/mL computed via weighted linear regression approach (1/x2). The proposed method could be applied to support the upcoming clinical studies for therapeutic drug monitoring of patients undergoing dual combination therapy as the latter combination proved more efficacious and powerful tool for the complete treatment of SARS-CoV-2 cases. Finally, the suggested bioanalytical method was efficiently utilized in human pharmacokinetic study of NHC and FAV, after simultaneous co-administration, in healthy volunteers.

An ultrahigh-performance liquid chromatography-tandem mass spectrometry method for quantification of methotrexate and 7-hydroxy-methotrexate and application for therapeutic drug monitoring in patients with central nervous system lymphoma.

A method using ultrahigh-performance liquid chromatography-tandem mass spectrometry was developed, validated, and applied to simultaneously determine plasma methotrexate (MTX) and 7-hydroxy-methotrexate (7-OH-MTX) in 117 patients with central nervous system (CNS) lymphoma. The ion transitions utilized were m/z 455.2 > 308.2 for MTX and m/z 471.2 > 324.1 for 7-OH-MTX. Samples were prepared through protein precipitation using methanol. Chromatographic separation was achieved within 3.0 min on a CMS9030 column (Ruixi, 2.1 × 50 mm, 3 μm) through a gradient elution of methanol and a 10% ammonium acetate solution at a flow rate of 0.4 mL/min. The method demonstrated linearity in the concentration range of 0.05-10 μM for MTX and 0.25-50 μM for 7-OH-MTX. The intra- and inter-day inaccuracy ranged from -7.38% to 7.83%, and the imprecision was less than 6.00% for both analytes. The recovery and matrix effect normalized by the internal standard (MTX-D3 ) remained consistent. Both analytes remained stable under nine different storage conditions. In patients with CNS lymphoma, MTX levels at 12 h and 7-OH-MTX levels at 12, 36, and 60 h after dosing in individuals with impaired renal function were significantly higher compared with those with normal renal function. 7-OH-MTX could potentially serve as a superior indicator for nephrotoxicity compared with MTX.

Clinical efficacy and safety of tigecycline based on therapeutic drug monitoring for carbapenem-resistant Gram-negative bacterium pneumonia in intensive care units

BackgroundWe investigated the associations between the different doses of tigecycline, its efficacy and safety, and the role of tigecycline therapeutic drug monitoring for patients in the intensive care unit.MethodsThis study was a single-center cohort including patients infected with multidrug-resistant Acinetobacter baumannii (MDR-AB) and multidrug-resistant Klebsiella pneumoniae (MDR-KP) causing pulmonary infections. The steady-state plasma concentration after tigecycline administration was determined by High-Performance Liquid Chromatography (HPLC) in patients admitted to the ICU between October 2020 and December 2021. Multivariate analyses of tigecycline’s clinical efficacy and safety were performed to control confounding factors.ResultsFor this study, we included 45 patients and 45 blood samples to determine steady-state trough concentrations of tigecycline. All patients were divided into the High Dose (HD) and Standard Dose (SD) groups. The median trough concentration of tigecycline was 0.56 μg/mL in the HD group, which was higher than in the SD group (0,21 μg/mL), p = 0.000. There was no significant difference between the two groups of patients in terms of bacterial eradication rate, mortality rate, and clinical efficacy. Multiple regression analysis showed that the ICU days were correlated with mortality OR 1.030(1.005–1.056), p = 0.017. APACHE II was significantly associated with clinical efficacy OR 0.870(0.755–1.002), p = 0.045. The level of fibrinogen decline in the HD group was significantly higher than in the SD group (-3.05 ± 1.67 vs -1.75 ± 1.90), p = 0.038. We identified that age and tigecycline treatment duration influenced fibrinogen decline.ConclusionsTigecycline plasma concentrations are significantly increased when using a high dose. However, the plasma concentration of tigecycline is not correlated with clinical efficacy and adverse reactions. Fibrinogen decline appears to be related to the patient’s age and days of tigecycline. Large sample data are still needed to confirm the clinical guidance significance of tigecycline TDM.

A Simple HPLC-UV Method for Ivosidenib Determination in Human Plasma.

Ivosidenib is used for the treatment of acute myeloid leukemia (AML) with isocitrate dehydrogenase 1 (IDH1) mutations. However, increased blood concentrations of ivosidenib are associated with a risk of a prolonged QT interval in patients with AML. Therapeutic drug monitoring in patients with AML with IDH1 mutation offers the potential to improve treatment efficacy while minimizing toxicity. In this study, we developed an efficient high-performance liquid chromatography-ultraviolet (HPLC-UV) method for the quantification of ivosidenib in plasma. Human plasma samples (50μL) were processed by protein precipitation using acetonitrile, followed by chromatographic separation on a reversed-phase column with an isocratic mobile phase of 0.5% KH₂PO₄ (pH4.5) and acetonitrile (45:55, v/v) at a flow rate of 1.0mL/min, with ultraviolet detection at 245nm. Calibration curves were linear over the range of 0.25-20μg/mL with a coefficient of determination (r2) of 0.99999. Intra-day and inter-day precision were 1.20-8.04% and 0.69-4.20%, respectively. The assay accuracy was -2.00% to 1.93% and recovery was >91.2%. These findings support the effectiveness of the newly developed HPLC-UV method for the quantification of ivosidenib in human plasma. This simple and cost-effective method is expected to expand ivosidenib monitoring in laboratories lacking LC-MS/MS instruments.

A Review of Therapeutic Drug Monitoring in Patients with Inflammatory Bowel Disease Receiving Combination Therapy.

Background: Inflammatory Bowel Disease (IBD) impacts millions worldwide, presenting a major challenge to healthcare providers and patients. The advent of biologic therapies has enhanced the prognosis, but many patients exhibit primary or secondary non-response, underscoring the need for rigorous monitoring and therapy optimization to improve outcomes. Objective: This narrative review seeks to understand the role of therapeutic drug monitoring (TDM) in optimizing treatment for IBD patients, especially for those on combination therapies of biologics and immunomodulators. Methods: A comprehensive synthesis of the current literature was undertaken, focusing on the application, benefits, limitations, and future directions of TDM in patients receiving a combination of biologic therapies and immunomodulators. Results: While biological therapies have improved outcomes, rigorous monitoring and therapy optimization are needed. TDM has emerged as a pivotal strategy, enhancing outcomes cost-effectively while reducing adverse events. While most data pertain to monotherapies, TDM's applicability also extends to combination therapy. Conclusion: TDM plays a crucial role in the treatment optimization of IBD patients on combination therapies. Further research is needed to fully understand its potential and limitations in the broader context of IBD management.

B-174 Simple and Accurate Quantification of Four Direct Oral Anticoagulants in Plasma Using UPLC-MS/MS

Abstract Background Direct oral anticoagulants (DOACs) constitute first-line therapy used for many thromboembolic indications, such as prevention and treatment of venous thromboembolism and stroke prevention in atrial fibrillation. This class of medication consists of the direct thrombin inhibitor (dabigatran) or direct factor Xa inhibitors (apixaban, rivaroxaban, and edoxaban). DOACs quantification may be useful in the case of critical clinical situations, including drug accumulation in long-term treatment, overdosage, thrombotic or bleeding events. This study aimed to develop and validate an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the quantification of four DOACs: dabigatran, apixaban, rivaroxaban, and edoxaban in plasma. Methods The calibration curve samples were prepared by spiking drug free plasma with DOACs. The stable isotope labeled DOACs was used as an internal standard. After addition of the internal standard and protein precipitation, the supernatant was 10-fold diluted and injected into a chromatography system consisting of a UPLC BEH C18 (2.1 × 50 mm; particle size 1.7 µm) analytical column with gradient made of mobile phase (5 mM ammonium formate pH3.5 in water and methanol). The outlet of the column was connected to a triple quadrupole mass spectrometer with electrospray interface. Ions were detected in the positive multiple reaction monitoring mode. The concentration of analyte was calculated from the calibration curve and ion ratios between the analyte and the internal standard. Results The analytical range was linear with a correlation coefficient of over 0.99 in the range of 0–500 ng/mL for each analyte. Intra- and inter-assay imprecision were less than 3.1% (n = 20) and 6.0% (n = 20), respectively. The accuracy was evaluated by spike recovery and the mean recoveries were between 97.2% and 102.1% for all analytes. This assay showed no ion suppression or enhancement and no carryover. The chromatography run time was 4.5 min. The assay was applied to quantitate DOACs in plasma samples from 93 patients. Our data showed that the DOACs concentrations vary markedly individual patients after equal dose, this therapeutic drug monitoring of DOACs is essential to optimized drug efficacy. Conclusion An accurate, and cost-effective UPLC-MS/MS method for the quantification of DOACs was successfully applied for therapeutic drug monitoring in patients.

Evaluation Of Vancomycin Therapeutic Drug Monitoring in Intensive Care Units of a University Hospital

Introduction and aim: Therapeutic drug monitoring (TDM) of vancomycin aims to achieve an optimal response and minimize the risk of toxicity by keeping plasma levels within the therapeutic range. In this study, we aimed to evaluate the treatment and appropriateness of TDM in patients receiving vancomycin. 
 Method: For this purpose, patients who received vancomycin in the ICUs of a university hospital during 8-month period between January and August 2022 were retrospectively evaluated. Demographic data, presence of renal dysfunction, length of stay, duration of treatment, dose, concomitant medications, presence of extracorporeal method, TDM, sampling time (trough and peak level) were collected. 
 Results: Within the scope of the study, 213 prescriptions of 202 patients were evaluated and it was revealed that TDM was performed in 18 (8%). A total of 26 trough (n=12) and peak (n=14) level were obtained. Three (25%) of the trough and eight (57%) of the peak samples were taken at the wrong time. 50% of the trough and 64% of the peak level results were outside the reference range. TDM was not performed in 174 patients taking nephrotoxic drugs concomitantly with vancomycin. There were 84 patients who developed acute kidney injury during treatment. TDM was performed in 10 (15%) of 65 patients with pretreatment renal dysfunction. 
 Conclusion: In order to minimize the risk of nephrotoxicity and to get the appropriate response, it is recommended that physicians should have a conscious approach, clinical pharmacists should take an active role and hospital pharmacists should make arrangements in the orders of patients who do not have TDM.

Pharmacological Treatments and Therapeutic Drug Monitoring in Patients with Chronic Pain.

Pain is an unpleasant sensory and emotional experience that affects every aspect of a patient's life and which may be treated through different pharmacological and non-pharmacological approaches. Analgesics are the drugs most commonly used to treat pain, and in specific situations, the use of opioids may be considered with caution. These drugs, in fact, do not always induce optimal analgesia in patients, and several problems are associated with their use. The purpose of this narrative review is to describe the pharmacological approaches currently used for the management of chronic pain. We review several aspects, from the pain-scale-based methods currently available to assess the type and intensity of pain, to the most frequently administered drugs (non-narcotic analgesics and narcotic analgesics), whose pharmacological characteristics are briefly reported. Overall, we attempt to provide an overview of different pharmacological treatments while also illustrating the relevant guidelines and indications. We then report the strategies that may be used to reduce problems related to opioid use. Specifically, we focus our attention on therapeutic drug monitoring (TDM), a tool that could help clinicians select the most suitable drug and dose to be used for each patient. The actual potential of using TDM to optimize and personalize opioid-based pain treatments is finally discussed based on recent scientific reports.

Standardization and validation of a novel UPLC-MS/MS method to quantify first line anti-tuberculosis drugs in plasma and dried blood spots

Tuberculosis (TB) is a high-burden infectious disease with high prevalence and mortality rates. The first-line anti-TB drugs include isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA), and ethambutol (EMB). At present, the standard method of blood sampling for therapeutic drug monitoring (TDM) analysis is venipuncture. Dried blood spots (DBS) are a minimally invasive method for collecting small quantities of whole blood from fingertips. The aim of the current study was to develop an ultrahigh-performance liquid chromatography technique coupled to tandem mass spectrometry (UPLC-MS/MS) for simultaneous quantification of the first-line anti-TB drugs in human plasma and DBS as a sampling alternative. The separation and detection conditions were optimized to quantify INH, RMP, PZA, and EMB in both matrices in an ACQUITY UPLC H Class system coupled to a XEVO TQD detector. Chromatographic separation was performed through an Acquity HSS T3 column (2.1 × 100 mm, 1.8 μm) with 0.1% formic acid in water and acetonitrile as the mobile phase. The total run time was 7 min for both methods, with retention time in plasma of 0.85, 1.22, 3.16, and 4.04 min and 0.74, 0.87, 0.97, and 4.16 min for EMB, INH, PZA, and RMP in DBS, respectively. The bioanalytical methods developed were proved selective, linear, precise, and accurate (inter- and intra-assay); the matrix effect was demonstrated to be within the established limits. Short- and long-term stability, freeze–thaw cycles for plasma, and short-term stability for DBS were established. A total of 15 patients with 46 ± 17 (mean ± SD) years old were included, and anti-TB drug concentrations were quantified on plasma and DBS as proof of concept. Based on RMP and INH plasma concentrations (Cp), and Bayesian estimation of individual pharmacokinetic parameters, a dose adjustment was necessary for 93% of patients. The slopes of the correlation lines between plasma and DBS concentrations of RMP, EMB, INH, and PZA were 0.5321, 0.8125, 0.5680, and 0.6791, respectively. Finally, significant correlations (p < 0.05) were observed between DBS and plasma concentrations for RMP (r2 = 0.6961), EMB (r2 = 0.4369), INH (r2 = 0.8675) and PZA (r2 = 0.7363). A simple, fast, and reliable UPLC-MS/MS method was developed to quantify first-line anti-TB drugs in plasma and DBS, which provides an easy sampling and storage to be applied as a new strategy for TDM in patients with TB.

Simultaneous and Rapid Determination of Plasma Concentrations of Four Tyrosine Kinase Inhibitors Using Liquid Chromatography/Tandem Mass Spectrometry in Patients with Non–Small Cell Lung Cancer

Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor commonly used in Japan. This study aims to develop a simultaneous rapid assay for gefitinib, erlotinib, afatinib, and osimertinib using liquid chromatography-tandem mass spectrometry (LC-MS/MS). These drugs in plasma samples were purified by liquid-liquid extraction with tert-butyl methyl ether, a simple and inexpensive method. The purified drugs were rapidly separated in less than 5 min by isocratic elution using an XBridge Shield RP18 column as the separation column and were sensitively quantified by MS/MS in the electrospray ionization positive mode. The quantification range in plasma for the four drugs was 5–200 nM with a linearity of >0.994 and a lower limit of quantification of 5 nM. The developed method was applied to therapeutic drug monitoring of patients with non–small cell lung cancer treated with oral osimertinib preparation and demonstrated its usefulness.

Therapeutic Drug Monitoring of Infliximab in Acute Severe Ulcerative Colitis.

Therapeutic drug monitoring (TDM) is a useful strategy in ulcerative colitis (UC). Nearly a quarter of UC patients will experience acute severe UC (ASUC) in their lifetime, including 30% who will fail first-line corticosteroid therapy. Steroid-refractory ASUC patients require salvage therapy with infliximab, cyclosporine, or colectomy. Fewer data are available for the use of TDM of infliximab in ASUC. The pharmacokinetics of ASUC make TDM in this population more complex. High inflammatory burden is associated with increased infliximab clearance, which is associated with lower infliximab drug concentrations. Observational data support the association between increased serum infliximab concentrations, lower clearance, and favorable clinical and endoscopic outcomes, as well as decreased rates of colectomy. Data regarding the benefit of accelerated or intensified dosing strategies of infliximab-as well as target drug concentration thresholds-in ASUC patients remain more equivocal, though limited by their observational nature. Studies are underway to further evaluate optimal dosing and TDM targets in this population. This review examines the evidence for TDM in patients with ASUC, with a focus on infliximab.

Simultaneous Determination of Rifamycin Antibiotics and Their Active Metabolites in Human Plasma Using UHPLC-MS/MS to Evaluate Their Impact on Target Peak Concentrations: A Short Communication.

Standard and proper antituberculosis (anti-TB) treatment is essential for patients with TB, and rifamycin antibiotics are key components of anti-TB therapy. Therapeutic drug monitoring (TDM) of rifamycin antibiotics can shorten the time to response and complete treatment of TB. Notably, antimicrobial activities of the major active metabolites of rifamycin are similar to those of their parent compounds. Thus, a rapid and simple assay was developed for simultaneous determination of rifamycin antibiotics and their major active metabolites in plasma to evaluate their impact on target peak concentrations. Here, the authors have developed and validated a method for simultaneous determination of rifamycin antibiotics and their active metabolites in human plasma using ultrahigh-performance liquid chromatography tandem mass spectrometry. Analytical validation of the assay was performed in accordance with the bioanalytical method validation guidance for industry described by the US Food and Drug Administration and the guidelines for bioanalytical method validation described by the European Medicines Agency. The drug concentration quantification method for rifamycin antibiotics, including rifampicin, rifabutin, and rifapentine, and their major active metabolites was validated. Significant differences in the proportions of active metabolites in rifamycin antibiotics may affect the redefinition of their effective concentration ranges in the plasma. The method developed herein is expected to redefine the ranges of "true" effective concentrations of rifamycin antibiotics (including parent compounds and their active metabolites). The validated method can be successfully applied for high-throughput analysis of rifamycin antibiotics and their active metabolites for TDM in patients receiving anti-TB treatment regimens containing these antibiotics. Proportions of active metabolites in rifamycin antibiotics markedly varied among individuals. Depending on the clinical indications of patients, the therapeutic ranges for rifamycin antibiotics may be redefined.

Accuracy of Therapeutic Drug Monitoring of Teicoplanin at the Onset of Febrile Neutropenia.

Background and Objectives: Teicoplanin (TEIC) is an effective drug for patients with febrile neutropenia (FN); however, it has been reported that these patients may have increased TEIC clearance compared with patients who do not have FN. The purpose of this study was to study therapeutic drug monitoring in patients with FN when the TEIC dosing design was based on the population mean method. Materials and Methods: Thirty-nine FN patients with hematological malignancy were included in the study. To calculate the predicted blood concentration of TEIC, we used the two population pharmacokinetic (population PK) parameters (parameters 1 and 2) reported by Nakayama et al. and parameter 3, which is a modification of the population PK of Nakayama et al. We calculated the mean prediction error (ME), an indicator of prediction bias, and the mean absolute prediction error (MAE), an indicator of accuracy. Furthermore, the percentage of predicted TEIC blood concentration within 25% and 50% of the measured TEIC blood concentration was calculated. Results: The ME values were -0.54, -0.25, and -0.30 and the MAE values were 2.29, 2.19, and 2.22 for parameters 1, 2, and 3, respectively. For all of the three parameters, the ME values were calculated as minus values, and the predicted concentrations tended to be biased toward smaller values relative to the measured concentrations. Patients with serum creatinine (Scr) < 0.6 mg/dL and neutrophil counts < 100/μL had greater ME and MAE values and a smaller percentage of predicted TEIC blood concentration within 25% of measured TEIC blood concentrations compared with other patients. Conclusions: In patients with FN, the accuracy of predicting TEIC blood concentrations was good, with no significant differences between each parameter. However, patients with a Scr < 0.6 mg/dL and a neutrophil count < 100/μL showed slightly inferior prediction accuracy.

Analytical Performance of the New Siemens Affinity Chrome-Mediated Immunoassay Everolimus Assay and Its Interchangeability With the Thermo Quantitative Microsphere System for Routine Therapeutic Drug Monitoring of Patients After Solid Organ Transplantation.

A new homogeneous affinity chrome-mediated immunoassay (ACMIA) "EVRO" from Siemens Healthcare was evaluated for therapeutic drug monitoring of everolimus (EVL) with automated sample pretreatment and compared with quantitative microsphere system (QMS) "EVER" from Thermo Fisher Scientific. Imprecision, inaccuracy, and limit of quantitation (LoQ) of ACMIA/EVRO were verified using both hemolysate quality control (QC) samples and pooled whole blood specimens. The interchangeability of methods and the agreement of results were analyzed using 72 specimens (from 38, 30, and 4 kidney, liver, and lung transplant recipients, respectively). Within-run imprecision ranged within %CV = 2.81-2.53 with pooled whole blood specimens and within %CV = 2.88-2.53 with QCs; total imprecision with QCs was within %CV = 2.14-1.51. Inaccuracy with value assigned QC was %△ = 5.36 at the 5.6 ng/mL level and %△ = 5.56 at the 11.7 ng/mL level. LoQ was 0.93 ng/mL (%CV = 10). Passing-Bablok regression showed a constant bias of 0.679 ng/mL (95% CI: 0.216-1.026) and a proportional bias of 1.326 (95% CI: 1.240-1.425). Bland-Altman analysis showed 5/72 (6.9%) paired differences exceeding the limits of agreement and 1/72 (1.4%) paired differences exceeding 1.96 SD to a combined bias of 39.9% after detrending. ACMIA/EVRO shows satisfactory analytical performances that comply with recommendations, but it does not fulfill requirements for interchangeability with QMS/EVER. Particularly, this new assay using sirolimus-specific antibody shows a sizable proportional bias versus the more specific comparator, which may be because of EVL metabolites. This is supported by the lack of agreement for individual differences in most samples collected at the peak concentration (C2). Therefore, further evidence is needed to support the transition of EVL level monitoring from QMS/EVER to ACMIA/EVRO without making extensive changes to both reference interval and patient's baseline.