Therapeutic Drug Monitoring最新文献

Background: This review re-evaluates therapeutic drug monitoring (TDM) by comparing the current analytical and subsequent clinical interpretation capabilities of hospital or community medical laboratories with the emerging potential of point-of-care (POC) devices, which could become increasingly utilized in hospital wards, day-hospital units, and outpatient clinic settings.

Methods: A narrative review was conducted to identify publications that best illustrate the current trends in the development of POC TDM.

Results: The latest scientific and technical literature indicates that POC devices for determining drug concentrations in clinical samples are approaching the market. Several technologies are now available to develop portable sensors capable of rapidly returning concentration measurements. Interfacing these methods with artificial intelligence-based pattern recognition may enhance the identification and quantification of drugs. However, once the drug concentration is accurately measured using a portable device, dosage adjustments require consideration of the drug's pharmacokinetics and the patient's characteristics. This is accounted for in the mathematical approaches underlying model-informed precision dosing, which consider inter- and intra-individual variability and provide recommendations for treatment adjustments. These complexities necessitate the use of digital technologies, including graphical interfaces, machine learning approaches, and secure connectivity, to enhance the application of TDM in clinical practice.

Conclusions: Promising emerging technologies have considerable potential to expand TDM to cover a wide range of drugs, making precision medicine accessible to many patients.

Background: Capillary blood microsampling enables the sampling of small blood volumes, making it suitable for vulnerable populations, remote collection, and repeated sampling. Owing to its minimal invasiveness, blood microsampling has emerged as an alternative to venipuncture in many fields. However, as capillary blood differs from venous blood in composition and analytes vary in their distribution between the blood cell and plasma fractions, plasma and capillary blood concentrations may differ. Because plasma is often the standard matrix for routine analyses, this discrepancy can compromise the clinicians' interpretation of capillary blood results. Hence, to ensure comparability with results obtained through plasma-based assays and reference ranges, accurate conversion to plasma concentrations may be required, which may improve the reliability and validity of microsampling-based outcomes. Despite its relevance, guidance on whether conversion is appropriate or desired and on how to translate and validate the translation of capillary blood microsampling results to plasma concentrations is lacking.

Method: To address this gap, members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) expert committees have prepared this guideline to discuss the "what, when, and how" of converting capillary to plasma concentrations and provide guidance on the decision of fit-for-purpose conversion. In addition, guidance to assess capillary blood results when the reference matrix is whole blood and to assess liquid capillary plasma results is provided. The included topics, as well as considerations and recommendations presented in this guideline, were based on a previously published dried blood spot-based IATDMCT guideline, literature review and expert opinions of the authors.

Results and conclusions: Key points include the importance of conducting a comprehensive clinical validation study to fully understand capillary blood microsampling results. In addition, the performance of the conversion method should be evaluated case by case, as it depends on both the microsampling-based method and analyte of interest. Furthermore, an independent set of paired capillary and venous samples should be used to validate an established conversion formula. Finally, a key point for future studies is to focus on the clinical impact of (converted) capillary blood concentrations in comparison with decisions based on results in the reference matrix to guarantee any microsampling-based outcome.

Background: The efficacy and toxicity of valganciclovir prophylaxis are determined by ganciclovir (GCV) exposure. As GCV is predominantly eliminated through glomerular filtration, kidney transplant recipients are at risk of both under- and overexposure. Kidney function is dynamic and GCV exposure may be off-target shortly after kidney transplantation and in kidney transplant recipients with delayed graft function (DGF). However, the extent of GCV under- and overexposure in the early phase after kidney transplantation has not been well described.

Methods: This was a retrospective, single-center analysis of adult patients who received valganciclovir prophylaxis and underwent at least one predose steady-state GCV concentration measurement during the first month after kidney transplantation. Data on GCV measurements, target attainment, and clinical outcomes, including cytomegalovirus (CMV) viremia and leukopenia, were collected and analyzed.

Results: Overall, 353 patients were included, with 357 predose and steady-state GCV concentration measurements. GCV exposure was highly variable early after kidney transplantation, especially in patients with poorly functioning grafts and those undergoing dialysis. Overall, there was a large proportion of patients with GCV exposure below the target, especially those with higher estimated kidney function, despite many receiving high GCV dosages. However, despite the frequent occurrence of off-target GCV exposure, no association was observed between DGF, GCV exposure, and CMV viremia.

Conclusions: In the early phase after kidney transplantation, exposure to GCV is highly variable among patients and underexposure to GCV occurs frequently. However, DGF was not associated with reduced exposure to GCV or CMV viremia, nor was early exposure to GCV correlated with CMV outcomes or leukopenia.

Background: Patients undergoing solid organ and hematopoietic stem cell transplantation are at risk of opportunistic pathogenic infections that increase morbidity and mortality. Universal antiviral prophylaxis improves the outcomes in this context. Therapeutic drug monitoring of antiviral drugs is not universally recommended but may be necessary in certain complex or polymorbid patients. The authors aimed to develop and validate a high-performance liquid chromatography-tandem mass spectrometry method to simultaneously quantify ganciclovir, acyclovir, and letermovir in human serum.

Methods: A stable isotopically labeled internal standard was used for each antiviral drug. Compounds were extracted by protein precipitation, evaporation, and reconstitution in an aqueous mobile phase. Samples were analyzed using reverse-phase chromatography with subsequent detection by electrospray ionization in the positive ion mode on a triple quadrupole mass spectrometer (run time: 6.5 minutes).

Results: Analytical curves for ganciclovir and acyclovir exhibited linearity within 0.1-25 mg/L (R 2 > 0.993), whereas for letermovir, the linear range was 0.01-2 mg/L (R 2 = 0.999). Matrix effects were not observed. Intraday and interday precision and accuracy were within ±15%. A therapeutic drug monitoring-guided strategy was explored to optimize preemptive antiviral drug therapy in 3 cohorts of transplant recipients. Seventy-nine samples from 35 patients were quantified, revealing median trough concentrations of 0.2 mg/L for ganciclovir (n = 21), 0.28 mg/L for acyclovir (n = 26), and 0.29 mg/L for letermovir (n = 32).

Conclusions: This method has been successfully applied in clinical settings and allows reliable and accurate drug-level measurements.

Background: Despite the general recommendation of AUC 0-24h /MIC ratio of 400-600 mg·h/L for vancomycin (VAN) effectiveness, there is no strong evidence of this index for patients undergoing renal replacement therapy (RRT). The aim of this scoping review was to summarize the scientific literature to assess the current evidence on VAN monitoring in hospitalized patients receiving intermittent hemodialysis (HD), identify gaps in knowledge, and guide future research.

Methods: A systematic search was performed using PubMed, Web of Science, Embase, LILACS, and the Cochrane Library databases based on keywords related to VAN, dialysis, and Therapeutic Drug Monitoring (TDM). References in the articles were also screened. The inclusion criteria were studies involving hospitalized adults undergoing intermittent HD, receiving intravenous VAN therapy, and with available TDM data.

Results: Systematic searches retrieved 297 articles, of which 21 were selected along with 1 from the reference screening, for 22 included studies. Clinical outcome data are still insufficient to determine the best VAN TDM parameters for patients undergoing intermittent HD. Target attainment was suboptimal in most settings regardless of the TDM method. The intradialytic removal of VAN is highly variable because of the combination of the RRT modality, RRT parameters, and dialyzer characteristics, which are often poorly described. The exact influence of the RRT parameters on intermittent RRT settings remains unclear.

Conclusions: The poor description of RRT, suboptimal VAN target attainment, and limited clinical outcome data in patients undergoing intermittent HD highlight the urgent need for further research. As VAN removal during RRT is influenced by a complex interplay of factors, improved dosing and monitoring strategies are required. In the future, model-informed precision dosing may play a significant role in optimizing VAN therapy in patients undergoing intermittent HD.

Background: Patients with suspected postoperative bacterial endophthalmitis are at a high risk of vision loss if not treated immediately and adequately. Initial treatment typically involves the intravitreal administration of antibiotics, with ceftazidime in combination with vancomycin being the common agents administered. Unbound ceftazidime exposure should exceed the minimum inhibitory concentration at the infection site. To facilitate investigation of the disposition of ceftazidime after its intravitreal injection, an ultra-performance convergence chromatography-tandem mass spectrometry method for quantifying ceftazidime in the vitreous humor was developed and validated in this study.

Methods: Each sample (20 µL) was prepared by protein precipitation of the test sample mixed with the internal standard solution (2 mg/L meropenem-d 6 in methanol). The sample was analyzed using a Waters Acquity UPC 2 system coupled to a Waters Xevo TQ-S micro triple quadrupole mass spectrometer (Waters Corp, Milford, MA). The method was validated according to guidelines published by the European Medicines Agency and US Food and Drug Administration. The validation parameters were linearity, limits of quantification (LOQs), accuracy, interday and intraday precision, carryover effect, autosampler stability, and short-term and long-term stability.

Results: The method had a linear range ( r2 > 0.990) between 1.3 and 99.6 mg/L and exhibited less than 15% inaccuracy and imprecision. The carryover effect was significant (53% of the lower LOQ) when injecting a blank sample after an upper LOQ sample but was negated after injecting an additional blank sample. Therefore, 1 blank sample should be injected after each patient sample.

Conclusions: This ultra-performance convergence chromatography-tandem mass spectrometry method facilitates the rapid and reliable determination of ceftazidime in the vitreous humor, with a short run time of 5 minutes. It was successfully applied to 72 clinical samples.

Purpose: This review focuses on antibiotic hypersensitivity, a clinically relevant issue owing to potentially severe adverse reactions. This review describes the classification, mechanisms of occurrence, and clinical manifestations of antibiotic hypersensitivity, and the diagnostic approaches. The aim was to provide recommendations for effectively treating reactions to antibiotics.

Methods: Publications, meta-analyses, and clinical cases related to antibiotic hypersensitivity were reviewed. Four types of antibiotic hypersensitivity were identified according to the Gell and Coombs classification.

Results: Type I [immunoglobin E (IgE)-mediated] antibiotic hypersensitivity manifests as anaphylaxis, urticaria, and bronchospasms. Type II (antibodies) causes cellular damage, resulting in thrombocytopenia or anemia. Type III antibiotic reactions are caused by immune complexes that induce inflammation. Type IV (T cells) is characterized by skin rashes or systemic symptoms. Pseudoallergies mimic allergic reactions without immune mechanisms and were separately considered. Accurate differential diagnosis is crucial in identifying true immune-mediated hypersensitivity reactions, which differ from pseudoallergic conditions, to avoid misdiagnosis and minimize patient risks associated with improper treatment or not administering necessary antibiotics. A detailed analysis of the mechanisms and clinical manifestations of antibiotic hypersensitivity allows the hypersensitivity type to be determined. Classical immunological reactions and reactions that mimic allergy but are not immune-mediated should be considered in diagnosis.

Conclusions: A comprehensive approach for diagnosing antibiotic hypersensitivity is required, which should include obtaining a thorough history, using modern laboratory methods (eg, skin, specific antibody, or basophil activation tests), and differentially analyzing clinical symptoms. Mimetic conditions, such as pseudoanaphylaxis or other pseudoallergic reactions that require different therapeutic approaches, must be considered as diagnoses in these cases.

Background: Therapeutic drug monitoring (TDM) is critical for optimizing drug efficacy and safety in precision medicine; however, conventional TDM methods rely on complex laboratory workflows. Consequently, there is an urgent need for fast, simple, and user-friendly technology to achieve point-of-care testing (POCT) for TDM. Aptamer-based sensors (aptasensors) have emerged as promising tools for point-of-care TDM because of their rapid response, high specificity, stability, and cost-effectiveness. This review summarizes the recent advances in aptasensor-based point-of-care TDM, analyzes current challenges, and explores future directions for enhancing clinical implementation.

Methods: This comprehensive review examined aptasensor applications in TDM, emphasizing innovations in sensor design, detection limits, and real-world applicability across various drug types. The literature for this review was searched using PubMed, Web of Science, and Google Scholar, covering publications up to 2024. Search terms included "aptamer," "biosensor," and "drug monitoring." Relevant studies focusing on the application of aptasensors in point-of-care TDM were included and analyzed.

Results: Aptasensors have demonstrated significant potential for point-of-care TDM by offering rapid and accurate drug monitoring. However, key challenges including limitations in scalable fabrication processes, inadequate clinical validation in diverse populations, and environmental interferences affecting sensor robustness remain.

Conclusions: Aptasensors hold a transformative potential for advancing point-of-care TDM, offering a pathway for personalized treatment optimization. Future efforts should prioritize rigorous clinical validation and improved stability in actual biological samples to fully realize their role in precision medicine.

Background: Predicting infliximab pharmacokinetics (PK) is essential for optimizing individualized dosing in pediatric patients with Crohn disease (CD). Machine learning (ML) has emerged as a tool for predicting drug exposure; however, its development typically requires large datasets. This study aimed to develop an ML model for infliximab PK prediction by leveraging population PK model-based synthetic and real-world data.

Methods: An initial ML model was trained using the XGBoost algorithm with synthetic infliximab concentration data (n = 560,000) generated from an established pediatric PK model. The prediction errors were assessed using real-world data, including 292 plasma concentrations from 93 pediatric and young adult patients with CD. A second XGBoost model, incorporating clinical features, was used to correct these errors. The performance of the model was evaluated using the root mean square error (RMSE) and mean prediction error (MPE).

Results: The first ML model yielded RMSE and MPE values of 6.44 and 1.84 mcg/mL, respectively. The features of the second XGBoost model included the predicted infliximab concentrations, cumulative dose, and dosing interval duration. A 5-fold cross-validation demonstrated improved performance of the ensemble model (RMSE = 4.30 ± 1.09 mcg/mL, MPE = 0.21 ± 0.39 mcg/mL) compared with the initial model and was comparable with the Bayesian approach (RMSE = 4.81 mcg/mL, MPE = -0.67 mcg/mL).

Conclusions: This study demonstrated the feasibility of combining synthetic and real-world data to develop an ML-based approach for infliximab PK prediction, potentially enhancing precision dosing in pediatric CD.

Background: Although the increased risk of piperacillin underexposure has been previously evidenced in intensive care unit patients with augmented renal clearance, it is still unclear whether the piperacillin dose could be a priori adapted according to renal function in these patients.

Methods: Steady-state concentrations (Css) of piperacillin were retrospectively collected from 159 adult intensive care unit patients who received a continuous infusion of piperacillin. Renal function was estimated for each patient using the Cockcroft-Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration 2021 formulas. The association between these formulas and the risk of piperacillin underexposure and overexposure (Css <80 and >157 mg/L, respectively) was investigated using receiver operating characteristic curves. The proportion of patients with piperacillin underexposure or overexposure to a 16 g/d regimen and the theoretical daily dose (DPDth) required to obtain a Css of 80 mg/L were calculated for 4 different creatinine clearance groups: 60-90, 90-130, 130-160, and >160 mL/min.

Results: Creatinine clearance calculated using the Cockcroft-Gault equation was a slightly better predictor of piperacillin underexposure and overexposure, with cutoff values of 128 and 81 mL/min, respectively. The percentage of patients with underexposure increased from 23% to 88% from the 60 to 90 to the ≥160 mL/min group, whereas the mean DPDth simultaneously increased from 13.9 to 30.8 g/d but with an important interindividual variability.

Conclusions: These results support a progressive increase in the daily dose of piperacillin with respect to renal function; however, the important interindividual variability precluded the determination of a robust dosing recommendation, making therapeutic drug monitoring mandatory.