Drug Concentration Monitoring Research Articles

A Single-Run HPLC-MS Multiplex Assay for Therapeutic Drug Monitoring of Relevant First- and Second-Line Antibiotics in the Treatment of Drug-Resistant Tuberculosis.

The treatment of drug-resistant Mycobacterium tuberculosis relies on complex antibiotic therapy. Inadequate antibiotic exposure can lead to treatment failure, acquired drug resistance, and an increased risk of adverse events. Therapeutic drug monitoring (TDM) can be used to optimize the antibiotic exposure. Therefore, we aimed to develop a single-run multiplex assay using high-performance liquid chromatography-mass spectrometry (HPLC-MS) for TDM of patients with multidrug-resistant, pre-extensively drug-resistant and extensively drug-resistant tuberculosis. A target profile for sufficient performance, based on the intended clinical application, was established and the assay was developed accordingly. Antibiotics were analyzed on a zwitterionic hydrophilic interaction liquid chromatography column and a triple quadrupole mass spectrometer using stable isotope-labeled internal standards. The assay was sufficiently sensitive to monitor drug concentrations over five half-lives for rifampicin, rifabutin, levofloxacin, moxifloxacin, bedaquiline, linezolid, clofazimine, terizidone/cycloserine, ethambutol, delamanid, pyrazinamide, meropenem, prothionamide, and para-amino salicylic acid (PAS). Accuracy and precision were sufficient to support clinical decision making (≤±15% in clinical samples and ±20-25% in spiked samples, with 80% of future measured concentrations predicted to fall within ±40% of nominal concentrations). The method was applied in the TDM of two patients with complex drug-resistant tuberculosis. All relevant antibiotics from their regimens could be quantified and high-dose therapy was initiated, followed by microbiological conversion. In conclusion, we developed a multiplex assay that enables TDM of the relevant first- and second-line anti-tuberculosis medicines in a single run and was able to show its applicability in TDM of two drug-resistant tuberculosis patients.

Development and Internal Validation of Machine Learning Algorithms for Determining Sodium Valproate Concentrations below the Standard Level Using a Risk Prediction Model of Children with Epilepsy

Background. There is a narrow therapeutic window for sodium valproate, and the blood concentration is too low to control epilepsy, while it is easy to poison the body if the concentration is too high. It is therefore necessary to monitor drug concentration reasonably in order to control epilepsy. The purpose of this study was to establish a model for predicting concentrations of sodium valproate below 50 μg/mL in children with epilepsy. Methods. The clinical data and biochemical examination results of children with epilepsy treated in the pediatric outpatient department of our hospital from June 2019 to March 2022 were retrospectively collected and divided into a development group and a validation group according to a patient ratio of 8 to 2. Five machine learning algorithms were used to identify the key variable factors, and a risk prediction model for sodium valproate blood concentrations lower than the standard concentration was established. The area under the curve (AUC), calibration curve, GiViTi calibration band, and clinical influence curve were used to evaluate the diagnostic efficacy and clinical application value of the model. Results. A total of 525 children with epilepsy were enrolled. In the development group, the random forest algorithm performed best in predicting that the blood concentration of sodium valproate was lower than the standard concentration, showing the highest AUC (1.00). Six factors were determined as a nomogram to predict the incidence of low concentrations. In the validation group and the development group, the calibration curve, GiViTi calibration band, and clinical influence curve all performed well in the evaluation of the diagnostic efficacy and clinical application value of the model. Conclusions. This finding highlights the importance of examining biochemical indices in patients when data regarding the blood concentration of sodium valproate are lacking.

Semiconductor-based biosensor exploiting competitive adsorption with charged pseudo-target molecules for monitoring 5-fluorouracil concentration in human serum

Rapid and simple monitoring of anticancer drug concentrations in blood is important for improving the efficacy of chemotherapeutic cancer treatment. In this study, we demonstrated the detection of 5-fluorouracil (5-FU) in human serum using a field-effect transistor (FET) biosensor with competitive adsorption between uncharged anticancer drugs and charged pseudo-targets. The target 5-FU and 5-FU-modified bovine serum albumin (BSA/5-FU) were competitively adsorbed on the FET sensor surface using antigen-antibody reaction with antigen-binding fragment (Fab) receptor. FET responses to the target 5-FU concentrations were obtained via changes in the amount of negatively charged BSA/5-FU captured by Fab molecules. In addition, the influence of serum components could be suppressed by diluting the samples with a nonionic surfactant solution. As a result, the FET biosensing system was capable of quantitatively detecting 5-FU concentrations in serum. Therefore, the semiconductor-based sensing system could enable the adjustment of anticancer drug dosages and potentially lead to improvements in anticancer drug therapy.

Quantitative evaluation of trace ritonavir in serum by versatile SERS substrate based on silver-decorated hollow reduced graphene oxide/zinc oxide nanotubes

Because of its fascinating molecular fingerprint identification ability and high sensitivity, surface-enhanced Raman scattering (SERS) shows an attractive application prospect in the clinical monitoring of blood drug concentration and efficacy judgment. In this study, a quantitative SERS-based detection of ritonavir in serum sample was conducted by developing silver (Ag)-decorated zinc oxide (ZnO)@reduced graphene oxide (rGO) nanotubes. Taking advantage of the efficient light absorption and molecular enrichment capabilities of hollow rGO-modified ZnO nanotubes with high specific surface area, an extremely low limit of detection (LOD) value of 466.7 pg/mL was achieved for ritonavir owing to the synchronous electromagnetic and chemical enhancement after the participation of Ag islands. Such a detection was carried out in a recyclable mode based on the intrinsic photocatalytic activity of ZnO, which was ascribed to the Ag and rGO-mediated effective separation of photo-induced electron-hole pairs. A practical SERS-based monitoring of ritonavir was finally facilitated in serum, demonstrating high recovery rates varied from 82.1% to 89.7%. Such a novel metal-semiconductor SERS sensor with ideal biocompatibility and sensitivity is promising in drug diagnostics.

Chiral pharmacokinetics of ibuprofen enantiomers in Chinese preterm neonates with patent ductus arteriosus using a validated UHPLC-MS/MS method

Persistent patent ductus arteriosus (PDA) is generally observed in preterm neonates. Oral ibuprofen is the standard treatment for closing PDA in China. To investigate the chiral pharmacokinetics of ibuprofen enantiomers in Chinese premature infants with PDA, a simple, fast, and sensitive analytical enantioselective technology was developed with ultra-performance liquid chromatography (UPLC) – tandem mass spectrometry (MS/MS). Chromatographic separation of (R)-ibuprofen and (S)-ibuprofen was accomplished on a Lux® 3 µm Cellulose-3 (150 mm × 2.0 mm, 3 μm) at a flow rate of 0.2 mL/min within 6 min. UPLC separation was achieved by isocratic elution with a mobile phase consisting of formic acid:water (75:1000000, v/v) and acetonitrile:methanol (1:1, v/v). Only 50 µL of plasma samples were pre-treated with acetonitrile precipitation. Ibuprofen-d3 was used as an internal standard. The standard curves of both enantiomers were linear over a concentration range of 0.0500 μg/mL to 50.00 μg/mL. The method has been validated for selectivity, carryover effect, lower limit of quantification, precision, accuracy, matrix effect, extraction recovery, dilution integrity, and stability based on the existing guidelines of the National Medical Products Administration, the United States Food and Drug Administration, and the European Medicines Agency. This method has been successfully applied to investigate the pharmacokinetics of ibuprofen enantiomers in 9 preterm infants with PDA. Our results showed that a high chiral inversion ratio of (R)- to (S)-ibuprofen exists in Chinese preterm neonates. Further studies should be conducted to monitor drug concentration following oral administration of ibuprofen and to consider the effect of individual variations and ethnic differences in metabolizing enantiomers of ibuprofen in premature neonates with PDA.

In situ construction of Fe3O4@PDA@Au multi hotspot SERS probe for trace detection of benzodiazepines in serum

The abuse of benzodiazepines is a serious health hazard that can cause damage to the central nervous system.Trace monitoring of benzodiazepines in serum can effectively prevent the damage caused by these drugs. Therefore, in this study, a Fe3O4@PDA@Au core–shell satellite nanomaterial SERS(Surface-Enhanced Raman Scattering) probe that integrates magnetic separation techniques and a multi-hotspot structure was synthetized by in situ growth of gold nanoparticles on the surface of PDA(Polymerized dopamine)-coated Fe3O4. The size and gap of Au nanoparticles on the surface of the SERS probe can be modulated by regulating the amount of HAuCl4 to create 3D multi-hotspot structures. The good dispersion and superparamagnetic properties of this SERS probe enable it to fully contact and load the target molecules in the serum, and the applied magnetic field facilitates separation and enrichment.This process increases the molecular density and number of SERS hotspots, thereby enhancing detection sensitivity. Based on the above considerations, this SERS probe can detect traces of eszopiclone and diazepam in serum at concentrations as low as 1 μg/ml with good linearity, offering promising applications in clinical monitoring of drug concentrations in blood.

Concomitant Treatment of Tuberculosis and Hepatitis C Virus in Coinfected Patients Using Serum Drug Concentration Monitoring.

Concern for drug-drug interactions leading to treatment failure and drug-resistant strains have discouraged clinicians from attempting concomitant treatment of hepatitis C virus (HCV) and tuberculosis (TB). Increased metabolism of direct-acting antivirals (DAAs) by rifamycins has hindered concurrent use. Development of an assay for ledipasvir and sofosbuvir (LDV/SOF) serum concentrations for therapeutic drug monitoring (TDM) can ensure adequate therapy. We present the first cases of concomitant therapy of active TB and HCV with rifamycin-containing regimens and DAAs using TDM. Using TDM, we aim to determine whether concomitant therapy with rifamycin-containing regimens and DAAs is safe and effective for patients coinfected with TB and HCV. Five individuals with TB and HCV who experienced transaminitis before or during TB therapy were concomitantly treated with rifamycin-containing regimens and LDV/SOF. Therapeutic drug monitoring was performed for LDV, SOF, and rifabutin during therapy. Baseline laboratory tests and serial liver enzymes were performed. Hepatitis C virus viral load and mycobacterial sputum cultures were obtained upon completion of therapy to determine efficacy of therapy. All patients were found to have nondetectable HCV viral loads and negative mycobacterial sputum cultures upon completion of therapy. No clinically significant adverse effects were reported. These cases illustrate concomitant use of LDV/SOF and rifabutin in patients with HCV/TB coinfection. Utilizing serum drug concentration monitoring to guide dosing, correction of transaminitis were achieved, which allowed the use rifamycin-containing TB therapy. These findings suggest that concomitant therapy of TB/HCV is possible, safe, and effective.

A strategy for low-cost portable monitoring of plasma drug concentrations using a sustainable boron-doped-diamond chip

On-site monitoring of plasma drug concentrations is required for effective therapies. Recently developed handy biosensors are not yet popular owing to insufficient evaluation of accuracy on clinical samples and the necessity of complicated costly fabrication processes. Here, we approached these bottlenecks via a strategy involving engineeringly unmodified boron-doped diamond (BDD), a sustainable electrochemical material. A sensing system based on a ∼1 cm2 BDD chip, when analysing rat plasma spiked with a molecular-targeting anticancer drug, pazopanib, detected clinically relevant concentrations. The response was stable in 60 sequential measurements on the same chip. In a clinical study, data obtained with a BDD chip were consistent with liquid chromatography–mass spectrometry results. Finally, the portable system with a palm-sized sensor containing the chip analysed ∼40 μL of whole blood from dosed rats within ∼10 min. This approach with the ‘reusable’ sensor may improve point-of-monitoring systems and personalised medicine while reducing medical costs.

Analytical validation of a novel UHPLC-MS/MS method for 19 antibiotics quantification in plasma: Implementation in a LC-MS/MS Kit

BackgroundTherapeutic drug monitoring (TDM) for antibiotic drugs represents a consolidated practice to optimize the effectiveness and to limit the toxicity of specific drugs by guiding dosage adjustments. The comparison of TDM results with drug-specific pharmacokinetic/pharmacodynamic (PK/PD) parameters, based on killing dynamics and bacterial susceptibility, increases the probability of therapeutic success. PurposeThe aim of this study was the analytical validation of a new UHPLC-MS/MS assay for the quantification of 19 antibiotics divided in two different sets considering their chemical/pharmacological properties. This method has been implemented in an analytical LC-MS/MS Kit System by CoQua Lab s.r.l (Turin). MethodsThe analytical validation is developed in accordance with “ICH Harmonized Guideline M10 on bioanalytical method validation and study sample analysis” and “Guidelines for regulatory auditing of quality management system of medical device manufacturers". Method suitability in the clinical context was tested by analysing clinical samples from patients treated with antibiotic drugs. ResultsThis method allows for simultaneous TDM of the following molecules: dalbavancin, daptomycin, linezolid, tedizolid, levofloxacin, moxifloxacin, meropenem, ertapenem, vaborbactam, avibactam, sulbactam, tazobactam, ceftazidime, ceftriaxone, ceftolozane, ceftobiprole, cefiderocol, ceftaroline and piperacillin. These drugs were quantified showing analytical performance parameters compliant with guidelines in terms of repeatability, reproducibility, robustness, bias, LOD, LOQ and linearity. The method was capable to successfully monitor drug concentrations in 65 samples from 52 patients undergoing treatment. ConclusionThe UHPLC-MS/MS method described in this work can be useful for TDM of the reported antimicrobial agents. The analytical protocol is rapid and suitable to be used in routine analysis.

Assessment of blend uniformity in a stream sampler device using Raman spectroscopy

This study describes the first implementation of Raman spectrometer in a stream sampler for the in-line monitoring of low drug concentration in poor flowability powder blends. Raman spectra were continuously acquired as the powder blends flowed through the stream sampler operating with a paddle wheel speed of 10 RPM and used to develop the calibration models. A calibration model was developed to quantify caffeine concentration from 1.50 to 4.50% w/w using Partial Least Squares Regression (PLS-R). Three test set blends were used to assess the prediction errors of the calibration model. Caffeine concentration was predicted for the test set blends with a root mean square error of prediction of 0.21% w/w and a low bias of −0.03% w/w. The calibration model showed good prediction performance with an estimated sample mass of 83 mg. Variographic analysis demonstrated the low process variance of the real-time spectral acquisition through minimum practical error and sill values. The results showed the ability of the Raman spectrometer coupled with the stream sampler to monitor low drug concentration for poor flowability blends.

Co-assembly of Ag nanowires and nanocubes mediated by adhesive tape in hydrophilic and hydrophobic pattern for SERS-based determination of gefitinib and ritonavir in serum

Controlled aggregation of noble metal nanoparticles is incredibly crucial for obtaining reliable surface-enhanced Raman scattering (SERS) properties. Here, a rational agglomeration of large Ag nanowires (NWs) and small Ag nanocubes (NCs) was readily facilitated by simply utilizing the intrinsic viscosity of adhesive tape, leading to the generation of abundant electromagnetic “hotspots” around the numerous crossed nanotips and ultra-small nanogaps. After the molecular enrichment efficiency was further promoted by exploiting a hydrophilic-hydrophobic strategy, an ultra-low limit of detection as 8.8 × 10−11 M was demonstrated for rhodamine 6 G. Benefiting from the high sensitivity of the SERS chip, its application in the determination of clinical sample containing mixed gefitinib and ritonavir was finally proved, facilitating impressive specificity and accuracy. Considering the simplicity and reliability, our strategy has great potentials to be applied in clinical blood drug identification and concentration monitoring.

The effect of combining therapeutic drug monitoring of antihypertensive drugs with personalised feedback on adherence and resistant hypertension: the (RHYME-RCT) trial protocol of a multi-centre randomised controlled trial

BackgroundAdherence to antihypertensive drugs (AHDs) is important for adequate blood pressure control. Not taking these drugs as prescribed is one of the main underlying causes for resistant hypertension (RH), which in turn leads to an increased risk of cardiovascular events, stroke and kidney damage. Therefore, correct identification of patients that are non-adherent to AHDs is crucial to improve clinical outcome. For this goal, therapeutic drug monitoring is the most reliable method. The primary objective of this trial is to investigate whether monitoring of drug concentrations with a dried blood spot (DBS) sampling method combined with personalised feedback leads to a decrease in prevalence of RH after 12 months due to an increase in adherence. Secondary objectives include the difference over time in the number of required AHDs as well as the defined daily dose (DDD). Lastly, the cost-utility of SoC versus the intervention in RH is determined.MethodsThis is a multi-centre single-blinded randomised controlled trial (RHYME-RCT). First, at an eligibility visit, DBS sampling, to monitor drug concentrations in blood, and a 24-h ambulatory blood pressure measurement (24-h ABPM) are performed simultaneously. Patients with a daytime systolic blood pressure (SBP) > 135 and/or diastolic blood pressure (DBP) > 85 mmHg are randomised to SoC or intervention + SoC. The intervention is performed by the treating physician and includes information on drug concentrations and a comprehensive personalised feedback conversation with the use of a communication tool. The follow-up period is one year with visits at 3, 6 and 12 months randomisation and includes 24-h ABPM and DBS sampling.DiscussionThis will be the first trial that focusses specifically on patients with RH without taking into account suspicion of non-adherence and it combines monitoring of AHD concentrations to identify non-adherence to AHDs with a comprehensive feedback to improve non-adherence. Furthermore, if this trial shows positive outcomes for the intervention it can be directly implemented in clinical practice, which would be a great improvement in the treatment of RH.Trial registration. RHYME-RCT is registered in the Dutch Trial Register on 27/12/2017 (NTR6914) and can be found in the International Clinical Trials Registry Platform.

Research Progress in Concentration Monitoring of Antipsychotic Drugs

Objective: To explore the drug concentration detection of antipsychotic drugs in the treatment of schizophrenia and other psychiatric diseases. Methods: Collecting the research results of relevant references in recent years, and summarizing the development and existing problems of the detection of psychotropic drugs in recent years from the perspective of drug detection methods, multidisciplinary integration, and interdisciplinary cooperation, so as to provide a reference for the follow-up monitoring of antipsychotic drugs. Results: It was found that the individual differences in pharmacokinetics of these drugs were large, and the side effects and toxic reactions were not easily distinguished from the aggravation of the symptoms of the disease itself. Conclusion: Through the analysis of the collected literature, we can understand the research progress of antipsychotic drug concentration monitoring, and provide strong evidence for the realization of clinical individualized precise treatment.

Management of Anti-Seizure Medications during Pregnancy: Advancements in The Past Decade.

Management of seizures often involves continuous medication use throughout a patient's life, including when a patient is pregnant. The physiological changes during pregnancy can lead to altered drug exposure to anti-seizure medications, increasing patient response variability. In addition, subtherapeutic anti-seizure medication concentrations in the mother may increase seizure frequency, raising the risk of miscarriage and preterm labor. On the other hand, drug exposure increases can lead to differences in neurodevelopmental outcomes in the developing fetus. Established pregnancy registries provide insight into the teratogenicity potential of anti-seizure medication use. In addition, some anti-seizure medications are associated with an increased risk of major congenital malformations, and their use has declined over the last decade. Although newer anti-seizure medications are thought to have more favorable pharmacokinetics in general, they are not without risk, as they may undergo significant pharmacokinetic changes when an individual becomes pregnant. With known changes in metabolism and kidney function during pregnancy, therapeutic monitoring of drug concentrations helps to determine if and when doses should be changed to maintain similar seizure control as observed pre-pregnancy. This review concentrates on the results from research in the past decade (2010-2022) regarding risks of major congenital malformations, changes in prescribing patterns, and pharmacokinetics of the anti-seizure medications that are prescribed to pregnant patients with epilepsy.

A Volumetric Absorptive Microsampling UPLC-MS/MS Method for Simultaneous Quantification of Tacrolimus, Mycophenolic Acid and Creatinine in Whole Blood of Renal Transplant Recipients.

(1) Background: Continuous monitoring of tacrolimus (TAC), mycophenolic acid (MPA), and creatinine (Cre) after renal transplantation is vitally important. In this study, we developed a new method based on volumetric absorptive microsampling (VAMS) combined with Ultra Performance Liquid Chromatography−Tandem Mass Spectrometry (UPLC-MS/MS) to simultaneously quantify three analytes including TAC, MPA, and Cre in whole blood. (2) Methods: The VAMS-based UPLC-MS/MS assay used a shared extraction and a single injection to simultaneously quantify the included TAC, MPA, and Cre. Development and validation were carried out following the Food and Drug Administration and European Medicines Agency guidelines for the validation of bioanalytical methods. Moreover, clinical validation for the three analytes was performed in both dried blood spot (DBS) and VAMS. Furthermore, a willingness survey was conducted using the system usability scale (SUS) for renal transplant recipients. (3) Results: The assay was successfully validated for all analytes. No interference, carryover, or matrix effects were observed, and extraction recoveries and process efficiencies were >90.00%. Analysis was unaffected by hematocrit (0.20~0.60, L/L) and anticoagulants (EDTA-2K). Dried VAMS samples were stable for 7 days at ambient temperature and stable for at least 1 month at −20 °C. During clinical validation, the measured TAC, corrected MPA, and Cre concentrations of VAMS samples met the analytical standards (95.00%, 88.57%, and 92.50%). When more stringent clinical acceptance criteria were set, the results obtained by VAMS (90.00%, 71.43%, and 85.00%) better than DBS (77.50%, 62.86%, and 70.00%). Compared with DBS, the survey found that renal transplant recipients are more inclined to use VAMS. (4) Conclusions: A robust extraction and UPLC-MS/MS analysis method in VAMS tips was developed and fully validated for the simultaneous quantification of TAC, MPA, and Cre concentrations. This method provides analytical support for the one-sample remote monitoring of both immunosuppressive drug concentrations and renal function in allo-renal recipients. Based on the good consistency between this method and the routine detection of venous blood samples and higher patient satisfaction than DBS, we believe that VAMS sampling can be a better alternative to venous whole-blood sampling.

MWCNTs-CTAB and HFs-Lac Nanocomposite-Modified Glassy Carbon Electrode for Rutin Determination.

Rutin is a flavonoid glycoside compound, which is mainly transported via the blood circulation system in the human body. The monitoring of the blood concentration of rutin is of great significance in many fields such as pharmacology and pharmacokinetics. In this work, a biosensor based on multi-walled carbon nanotubes (MWCNTs), cetyltrimethylammonium bromide (CTAB), hydroxyl fullerenes (HFs), and laccase (Lac) nanocomposite-modified glassy carbon electrodes was constructed. The modified materials were characterized with a transmission electron microscope (TEM), cyclic voltammograms (CV), and electrochemical impedance spectroscopy (EIS). CTAB is used to disperse MWCNTs and improve hydrophilicity and biocompatibility of MWCNTs, while the use of Lac can enhance the oxidation of catechol structure in rutin, thus significantly improving the sensitivity and selectivity of the modified electrode. Linear sweep voltammetry (LSV) studies showed that the determination linear ranges of rutin were 0.1 µmol L−1 to 2 µmol L−1 and 2 µmol L−1 to 11 µmol L−1, with the determination limits of 30 nmol L−1 and 95.5 nmol L−1, respectively. The proposed biosensor can be used to detect rutin tablets and serum samples with high recovery, which indicates a good accuracy of this method, and the results are consistent with those measured by the traditional ultra-high performance liquid chromatography (UHPLC) method. Hence, this biosensor has potential practical application value in rutin drug quality testing and clinical blood drug concentration monitoring.

Simultaneous Determination of Six Immunosuppressants in Human Whole Blood by HPLC-MS/MS Using a Modified QuEChERS Method.

A high-performance liquid chromatography-tandem mass spectrometry method was established for the simultaneous determination of mycophenolic acid, mycophenolate mofetil, tacrolimus, rapamycin, everolimus and pimecrolimus in human whole blood by optimizing the QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) preparation method. Whole blood was extracted into ethyl acetate, salted out with anhydrous magnesium sulfate, and purified with ethylenediamine-N-propyl silane adsorbent. The supernatant was evaporated under nitrogen until dry and finally reconstituted in methanol. Chromatographic separation was performed on an Agilent Poroshell 120 EC-C18 column in methanol (mobile phase A)-water (optimized for 0.1% acetic acid and 10 mM ammonium acetate, mobile phase B) at a 0.3 mL·min−1 flow rate. Electrospray ionization and positive ion multiple reaction monitoring were used for detection. The time for of analysis was 13 min. The calibration curves range of tacrolimus, rapamycin, everolimus and pimecrolimus were in the range of 1–100 ng·mL−1, mycophenolate mofetil in the range of 0.1–10 ng·mL−1 and mycophenolic acid at 10–1000 ng·mL−1. All correlation coefficients were >0.993. The coefficients of variation (CV, %) for inter-day and intra-day precision were less than 10%, while the spiked recoveries were in the range of 92.1% to 116%. Our method was rapid, sensitive, specific, and reproducible for the simultaneous determination of six immunosuppressants in human whole blood. Importantly, our approach can be used to monitor drug concentrations in the blood to facilitate disease treatment.

Risk factors for development of hematotoxicity in elderly patients treated with Linezolid

Objective: To analyze the clinical data, especially the occurrence of hematotoxicity, of hospitalized elderly patients who took Linezolid (LZD), and to further explore the related risk factors. Methods: Our study enrolled the elderly inpatients treated with linezolid at the Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School from January 2018 to September 2021. The hospital information system data were retrieved to retrospectively analyze the clinical characteristics of patients, particularly the clinical characteristics and related risk factors of patients who experienced hematotoxic reactions to LZD. Results: Of the 233 eligible cases included, 103 patients received empirical use of LZD (44.21%). The total effective rate was 76.39% (178/233). Among the 57 effective cases who received blood drug concentration monitoring, the trough concentration of LZD was high in 36.84 % (21/57) of elderly patients. Moreover, there were 15 patients with thrombocytopenia alone, 3 patients with decreased hemoglobin (HB) alone, and 3 patients with both thrombocytopenia and HB decrease. The patients who experienced hematotoxicity (developed a certain degree of hemoglobin decrease and/or thrombocytopenia) were more likely to be complicated with renal impairment (χ²=6.642, P=0.036), concomitantly using proton pump inhibitor (PPI) (χ²=4.566, P=0.033), and had a longer course of LZD treatment (P=0.041). There was no linear correlation between the trough concentration of LZD and glomerular filtration rate evaluated by Modification of Diet in Renal Disease Formula (eGFRMDRD) (R=0.226, P=0.136). Conclusions: The elderly patients, especially those with renal impairment, concomitant treatment with PPI, and a longer course of LZD treatment, exhibited a higher risk of hematotoxicity during LZD treatment. Hence, we should strengthen the protection of renal function, reduce drug interaction, and dynamically monitor the blood drug concentration of LZD to adjust its dose, thus implementing safer and more effective treatments.

LC-MS/MS quantification of levetiracetam, lamotrigine and 10-hydroxycarbazepine in TDM of epileptic patients.

To minimize drug-related toxicity and monitor dosing regimens, an ultra-sensitive, simple and high-throughput analytical method for therapeutic drug monitoring is required. A novel LC-MS/MS bioassay of levetiracetam, lamotrigine and 10-hydroxycarbazepine in human plasma was established. The analytes were separated on a Hypersil GOLD™ C18 column under a 2.5 min isocratic elution after one-step protein precipitation. MS detection was performed under electrospray ionization positive-mode fitted with selected reaction monitoring. The validated ranges were 0.1-20 μg/ml for LTG, 0.3-60 μg/ml for 10-hydroxycarbazepine and levetiracetam. The intra- and inter-batches of precision and accuracy was within ±15%. The novel method met all other criteria. This method can be used to monitor drug concentrations and decision-making in epileptic patients.

A European cross-sectional survey to investigate how involved doctors training in clinical pharmacology are in drug concentration monitoring

PurposeTherapeutic drug monitoring (TDM) is widely recognised as a key attribute of clinical pharmacologists; yet, the extent to which physicians undertaking postgraduate training in clinical pharmacology (hereafter trainees) are involved in TDM is poorly characterised. Our own experience suggests wide variation in trainee exposure to TDM.MethodWe performed a Europe-wide cross-sectional internet-based survey of trainees to determine the nature and extent of trainee involvement in TDM.ResultsThere were 43 responses from eight countries analysed. Of the 21 respondents from the UK, all were also training in general internal medicine (GIM), while all of the respondents who were solely training in clinical pharmacology were from outside the UK. Overall, 86.0% of respondents reported access to drug monitoring for clinical care at their affiliated institution, of which 81.0% were personally involved in TDM in some capacity. On average, trainees reported that drug monitoring was available for 16 of the 33 (48%) of the drug/drug classes surveyed. UK-based respondents were involved in requesting drug-level investigations and interpreting the results for patients under their care in 76.2% and 85.7% of cases, respectively, while non-UK respondents supported other healthcare professionals to interpret results in 45.4% of cases. Trainees felt TDM training was generally either insufficient or very inadequate.ConclusionWhile access to TDM is relatively available at institutions where trainees are based, the role of trainees is variable and affected by a variety of factors including country and training programme. Universally, trainees feel they need more education in TDM.