Therapeutic Drug Monitoring最新文献

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.

Background: Eculizumab is effective in treating paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Given its high cost and the clinical risks associated with undertreatment or overtreatment, dose individualization is essential. Model-informed precision dosing can optimize therapy using pharmacokinetic (PK) model predictions. This study conducted a primarily internal validation to evaluate the predictive performance of a previously published PK model of eculizumab for model-informed precision dosing.

Methods: The model's ability to predict future free trough concentrations was assessed using retrospective data from therapeutic drug monitoring. Acceptable bias and precision were defined as mean prediction error and normalized root mean square error less than 25%. Dose adjustments were evaluated based on target trough concentrations of 50 µg/mL for dose escalation and 200 µg/mL for interval extension.

Results: The model adequately predicted future trough concentrations. In patients with paroxysmal nocturnal hemoglobinuria, bias and precision were -3.0% and 10.3%, respectively, when using one trough concentration; -8.4% and 24.9%, respectively, when using a trough and a peak concentration; and -4.7% and 16.3%, respectively, when using two trough concentrations. In patients with atypical hemolytic uremic syndrome, bias and precision were 6.1% and 35.5%, respectively, when using one trough concentration; 15.1% and 25.7%, respectively, when using a trough and a peak concentration; and 11.2% and 23.2%, respectively, when using two trough concentrations. The model's predictions led to correct dose recommendations for >80% of patients in most analyses.

Conclusions: These results demonstrate that the eculizumab PK model can predict future trough concentrations with acceptable bias and precision.

Aim: The aim of this study was to present summary data from a serum clozapine proficiency testing scheme.

Methods: Monthly returns submitted to the LGC Standards clozapine and norclozapine proficiency testing scheme between 2012 and 2024 were analyzed.

Results: A total of 191 participating laboratories participated, of which 164 reported norclozapine results. From 2013 to 2024, the number of returns per distribution was 85. The proportion of laboratories using liquid chromatography-mass spectrometry increased over time and reached 74% in 2024, while the use of high-performance liquid chromatography decreased. Thirteen distributions contained neither analyte; however, 76 returns (6.8%) reported detectable clozapine concentrations (median 10.4, range 0.01-518.73 mcg L-1). In 22 distributions, clozapine concentrations >10 mcg L-1 (median 151.63, range 30.3-2175.25 mcg L-1) were detected but reported as "0" or below the lower limit of quantification. Comparable findings were observed for norclozapine. No temporal differences in quantitative performance, assessed using z-scores, were observed between analytical methods. Median clozapine z-scores were further from zero when clozapine alone was measured than when both clozapine and norclozapine were measured.

Conclusions: Increased use of liquid chromatography-mass spectrometry was not associated with improved analytical performance for clozapine or norclozapine. Method validation should include assessment of potential interference from metabolites and coadministered drugs. Unexpected results require repeat analysis or repeat sampling when clinically feasible.

Background: Dried blood spot (DBS) sampling is considered an alternative sampling strategy for therapeutic drug monitoring (TDM) in patients receiving outpatient parenteral antimicrobial treatment (OPAT). This study was conducted to identify the barriers and facilitators of DBS sampling for patients receiving OPAT.

Methods: Patients undergoing DBS sampling for TDM of vancomycin in the OPAT setting were qualitatively evaluated. Patients were interviewed using a semistructured interview guide; patient inclusion ceased when data saturation was achieved. The results were transcribed verbatim and analyzed inductively by 2 researchers using thematic analysis.

Results: Eight patients were interviewed. Fifteen barriers and 15 facilitators were classified in 4 domains: information, technique, process, and patient. The overall view of DBS sampling was positive. Patients described the added value of DBS sampling for health care in terms of health care personnel and time. Involvement in their own health care was also mentioned as a positive attribute of DBS sampling. Facilitators included training that provided information on warming the hands, DBS properties (simple and quick to perform, easy integration in routine, time and cost saving), and previous experience with the finger prick procedure. A patient's sense of responsibility is crucial for successfully performing DBS. Barriers included insufficient information on the background of DBS sampling, limitation of assays available for DBS sampling, posting and mail delivery, and aversion toward needles.

Conclusions: Barriers and facilitators of DBS sampling for TDM were identified in the OPAT setting, providing insight for proper DBS implementation.

Background: Posaconazole is an antifungal agent used to prevent or treat invasive fungal infections (IFIs) in critically ill patients, including those receiving extracorporeal membrane oxygenation (ECMO). However, in vitro data suggest that posaconazole is extensively sequestered in ECMO circuits. The aim of this study was to determine the impact of ECMO on posaconazole concentrations in critically ill patients.

Methods: The authors conducted a retrospective cohort study involving patients receiving intravenous posaconazole in the intensive care unit from January 2014 to July 2024. Posaconazole concentrations at the first sampling and the proportion of patients achieving target concentrations for prophylaxis (>0.7 mg/L) and treatment (>1 mg/L) of IFI were assessed. Patients receiving ECMO were compared with non-ECMO patients. In addition, the impact of ECMO initiation or decannulation on posaconazole concentrations was examined.

Results: In total, 19 patients (8 ECMO and 11 non-ECMO) were included. ECMO patients had lower posaconazole concentrations (median [interquartile range], 0.7 [0.5-0.7] mg/L versus 1.2 [0.7-1.4] mg/L, P = 0.04) and were less likely to reach therapeutic concentrations (13% versus 64%, P = 0.04). Fewer ECMO patients achieved concentrations required for prophylaxis, although this difference was not statistically significant (50% versus 82%, P = 0.17). ECMO initiation was associated with a reduction in posaconazole concentration (n = 1), whereas decannulation was associated with an increase (n = 3).

Conclusions: ECMO patients may be at an increased risk of subtherapeutic posaconazole concentrations for treating IFI, and ECMO decannulation may increase concentrations. Close therapeutic drug monitoring is recommended, especially during ECMO initiation and decannulation, to ensure posaconazole concentrations are appropriate for treating or preventing IFI.

Background: Intentional sodium nitrite poisoning is an emerging trend worldwide, as it is promoted for its use in self-euthanasia. Nitrite dipstick urinalysis could potentially serve as a rapid-diagnostic tool. Urine dipstick analysis is a common point-of-care test (POCT) for the initial diagnosis of urinary tract infections. The aim of this study was to investigate nitrite dipstick urinalysis as a potential reliable POCT for the early detection of sodium nitrate poisoning.

Methods: Postmortem urine samples, collected over 1 year, were prospectively analyzed for nitrite presence using a urine dipstick method. In addition, a retrospective search was conducted in the database to identify cases with suspected or confirmed sodium nitrite poisoning as the cause of death. Available urine samples from these cases were screened for the presence of nitrite.

Results: Prospectively, 10 of the 420 urine samples tested positive for nitrite presence: 6 samples without any suspicion of sodium nitrite ingestion and 4 with confirmed sodium nitrite poisoning as the cause of death. In addition, in our retrospective study, 12 cases of suspected sodium nitrite poisoning were tested for nitrite presence in the urine using the dipstick. Of these, 8 tested positive for nitrite. Two of the 12 cases were later attributed to intoxication with other substances. As a control, urine samples spiked with sodium nitrite were tested using the dipstick; the pink color intensified with increasing sodium nitrite concentration.

Conclusions: Nitrite dipstick urinalysis is a feasible approach for the early detection of nitrite poisoning in postmortem toxicological screening. In addition, this rapid POCT shows potential as a diagnostic tool for use in acute clinical settings in cases of suspected sodium nitrite poisoning or elevated methemoglobinemia with an unknown cause.

Background: The constant emergence of novel psychoactive substances (NPS) poses significant analytical challenges due to their structural diversity, low concentrations in complex biological matrices, and the limited availability of certified reference materials. This review summarizes current and emerging analytical strategies for detecting novel substances and evaluates the contribution of innovative technologies for toxicological surveillance.

Methods: Studies addressing analytical techniques for NPS detection including chromatographic, spectrometric, ambient ionization, and artificial intelligence (AI)-assisted methods were systematically reviewed, with emphasis on applicability, sensitivity, and adaptability in clinical, forensic, and environmental contexts.

Results: Conventional techniques such as liquid chromatography coupled with tandem mass spectrometry and immunoassays provide reliable detection of known compounds but are limited by their targeted scope for detecting newly synthesized analogs. High-resolution mass spectrometry, nuclear magnetic resonance, and direct ionization approaches offer broader detection capabilities but remain resource-intensive. Recent advances in AI-including spectral prediction, structural classification, and de novo compound generation-offer promising new avenues for untargeted screening and early compound identification. In addition, emerging tools such as molecular networking, wastewater-based epidemiology, and portable mass spectrometry devices further enhance real-time monitoring and surveillance capacity.

Conclusions: An integrated, adaptive analytical framework combining high-resolution mass spectrometry, ambient ionization, and AI-driven data analysis will help address the fast-evolving NPS landscape. Standardization of reference materials, harmonization across laboratories, and interdisciplinary collaboration between chemists, clinicians, and regulatory agencies will be key to improving the speed, sensitivity, and public health impact of NPS detection.