Therapeutic Drug Monitoring最新文献

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.

Background: With the patchwork legalization of cannabis in the United States and the loopholes surrounding "legal" highs, the prevalence of Δ8-tetrahydrocannabinol (Δ8-THC) has been rising, requiring the development of methods to extract, differentiate, and detect it separately from Δ9-tetrahydrocannabinol (Δ9-THC) and its metabolites. The authors focused on developing a method to detect the primary metabolite Δ8-carboxy-tetrahydrocannabinol (Δ8-THC-COOH) separately from Δ9-carboxy-tetrahydrocannabinol (Δ9-THC-COOH) in urine, a commonly collected sample in human performance toxicology.

Methods: Liquid-liquid extraction with hydrolysis was used to isolate and extract metabolites from forensic urine samples. After evaporation, the extract was flash-derivatized using an MTBSTFA:ACN (1:3) solution, followed by gas chromatography-mass spectrometry analysis. The results were tabulated and subjected to statistical analysis.

Results: Forensic human performance urine specimens (n = 127) were analyzed for ∆8-THC-COOH, ∆9-THC-COOH, and 7-carboxy-cannabidiol (7-COOH-CBD) between January 2023 and January 2024. In total, 52 samples contained only ∆9-THC-COOH, 70 contained both ∆8-THC-COOH and ∆9-THC-COOH, 3 contained only ∆8-THC-COOH, and 5 contained both 7-COOH-CBD and ∆9-THC-COOH, with 3 of these containing all 3 metabolites. The area abundances of their respective chromatographic peaks was used to calculate the ∆8:∆9 metabolite ratio when both ∆8-THC-COOH and ∆9-THC-COOH were detected. Despite a higher mean ratio in driving under the influence cases (13.87 versus 8.53), the difference between the mean values was not statistically significant (independent-sample t test: t (68) = -0.670, p = 0.505).

Conclusions: This study and its methodology provide insight into the effective separation and analysis of the compounds of interest, and discuss the potential differentiation of ∆8-THC-dominant products from traditional cannabis, and underscore the prevalence of ∆8-THC and ∆8-THC-dominant products in the current market, while highlighting the need for further studies on this topic.

Background: Antidotes play a crucial role in medical toxicology, providing life-saving interventions against a wide range of toxic substances. Despite their long-standing use, new evidence suggests that fomepizole, l-carnitine, and naloxone may have a wider range of applications than previously thought. This manuscript aims to review the emerging evidence for new treatment indications for fomepizole, l-carnitine, and naloxone.

Methods: A narrative literature review was conducted to inform clinicians and researchers about the evolving practices of antidote therapy and to identify areas where further research is warranted to optimize patient outcomes.

Results: Fomepizole has proven its service in the treatment of toxic alcohol poisoning. The inhibitory action of fomepizole on the CYP2E1 and JNK pathways opens new avenues for its application as an antidote for a broader panel of intoxications, including paracetamol poisoning. In addition to l-carnitine supplementation to restore valproic acid-induced carnitine deficiency after chronic use or overdose, many other benefits have been attributed to l-carnitine supplementation for the treatment of drug intoxication. The antioxidative effects of carnitine and its role in promoting fatty acid β-oxidation via the mass effect are less well established. Finally, naloxone is known for its antagonistic action in cases of opioid overdose. Regarding novel indications, the most compelling evidence for naloxone as an antidote was found for clonidine and angiotensin-converting enzyme inhibitors.

Conclusions: The repurposing of antidotes such as fomepizole, l-carnitine, and naloxone represents a promising frontier in precision toxicology. As the understanding of molecular toxicology deepens, it is becoming increasingly feasible to match antidotes to specific molecular signatures of toxicity, rather than relying solely on syndromic classifications.

Background: High-dose methotrexate is widely used in chemotherapy for malignant tumors. This study explores the correlation between methotrexate (MTX) and 7-hydroxy methotrexate (7-OHMTX) concentrations and indicators of liver and kidney function while evaluating the predictive value of MTX and 7-OHMTX levels for delayed elimination.

Methods: The authors collected 372 blood samples from 107 leukemia or lymphoma patients (45 adults and 62 children) treated with high-dose methotrexate. The free and total concentrations of MTX and 7-OHMTX were measured 48, 72, or 96 hours after chemotherapy administration. SPSS 27 software was used to analyze the Spearman correlation between concentration and liver and kidney indicators. The nonparametric Mann-Whitney U test was used to compare the Normal and Delayed groups. Receiver operating characteristic curve analysis identified the threshold for delayed elimination.

Results: The total 7-OHMTX concentration did not correlate with creatinine clearance (CCR) and creatinine (CR) in children. The free 7-OHMTX concentration showed a significant negative correlation with CCR (P < 0.01) and a positive correlation with CR (P < 0.01) in children and in subgroup A2 (7-12 years). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly negatively correlated with both total and free 7-OHMTX/MTX concentrations in children (P < 0.01). MTX and 7-OHMTX concentrations showed no correlation with CR, CCR, AST, or ALT in adult patients.

Conclusions: Clinicians should closely monitor patients for signs of elimination delay when free 7-OHMTX concentrations exceed 0.081 μmol/L 48 hours or later. Incorporating free-concentration monitoring predicts hepatotoxicity and nephrotoxicity in children more accurately than total concentrations alone, facilitating timely clinical intervention and ensuring patient safety.