Therapeutic Drug Monitoring最新文献

Background: Rituximab is commonly used to treat patients with primary glomerular diseases; however, its pharmacokinetics in this population have not been fully described yet.

Materials and methods: This single-center, open-label, uncontrolled clinical trial included adult patients with glomerular diseases who required rituximab treatment (NEFRTX; EudraCT: 2020-000484-23). Patients received 1 or 0.5 g of rituximab on day 1 (and d14 in some cases). Blood and urine samples were collected at days 1, 7, 14, 28, and 45 to measure biochemical parameters (proteinuria, albuminemia, plasma immunoglobulin, and urine immunoglobulin), rituximab, and antidrug antibody concentrations. The gene encoding the neonatal fragment-crystallizable receptor was also characterized. Linear regression and Win-Nonlin 1.1 were used for pharmacokinetic analysis.

Results: Thirty-five cases (30 patients) were included in this study. Pharmacokinetic parameters were expressed as mean (SD): maximum plasma concentration, 179.4 (71.8) mcg/mL; volume of distribution, 78.9 (31.4) mL/kg; clearance, 0.30 (0.27) mL/h/kg; half-life (t 1/2 ), 11.6 (5.8) d; elimination rate constant, 0.0036 (0.0030) hour -1 ; and area under the curve, 117,756.1 (88,228.1) mcg·h/mL. Antidrug antibody was detected on d1 in 3 cases (8.6%) and was negative by d28.Rituximab t 1/2 was represented by the formula: t 1/2 = A-B·Log (Proteinuria)+C·Albuminemia, where A = 515.1 (128.8-901.3), B = 182.1 (-108.6 to -35.4), and C = 39.5 (-10.9 to 89.9).There were significant differences in rituximab t 1/2 based on diagnosis ( P = 0.025), early treatment ( P = 0.008), proteinuria >2.4 g /24h ( P < 0.001), plasma immunoglobulin <650 mg/dL ( P = 0.048), and detectable urine immunoglobulin ( P = 0.018).

Conclusions: Albuminemia and proteinuria affect rituximab t 1/2 and drug exposure in patients with glomerular diseases. Patients with proteinuria >2.4 g /24h may require higher frequent dosing for adequate rituximab exposure. Establishing an optimal dosing regimen in this population remains warranted.

Background: The introduction of oral targeted anticancer drugs has revolutionized anticancer treatments. Exposure to these drugs is often affected by individual, disease, or drug characteristics. As a result, these drugs often show high interpatient variability in drug exposure. Therapeutic drug monitoring (TDM) is a useful tool for addressing the underlying problems of this variability: unnecessary toxicity and suboptimal efficacy. In this overview article, the authors discuss achievements, experiences, and current challenges of TDM for oral targeted anticancer drugs in clinical practice and highlight directions for future research.

Methods: PubMed was searched for relevant clinical studies on TDM of oral targeted anticancer drugs.

Results: TDM for oral targeted anticancer drugs should be routinely conducted when exposure-response or exposure-toxicity relationships are established to avoid underexposure or overexposure, and on indication, to achieve reasonable drug exposure in individual cases when exposure is suspected to be outside the therapeutic index. The current challenges in supporting TDM for oral targeted anticancer drugs include the absence of compelling prospective evidence on clinical outcomes and the paucity of pharmacokinetic data for newly approved drugs. Future studies should address these issues.

Conclusions: Advancing TDM of oral targeted anticancer drugs requires finding the right drugs, the right patients, the right drug exposure targets, the right sampling methods, and the right evidence. Addressing these issues can facilitate clinical implementation and ensure that TDM can be applied for both older and newly approved oral targeted anticancer drugs.

Background: High-dose methotrexate (HDMTX) is a cornerstone therapeutic regimen for hematological malignancies; however, delayed elimination remains a significant clinical challenge. Currently, no standardized definition for delayed elimination exists. This scoping review aims to identify and characterize methotrexate elimination threshold variability and its implication on clinical data interpretation.

Method: A literature search was conducted using PubMed, Scopus, and the Cochrane database to identify studies published in English from the 1960s to February 2025. All study types reporting delayed elimination thresholds for high-dose methotrexate in adult patients with hematological malignancies were included.

Result: Twenty-three studies meeting the inclusion criteria were charted and summarized. The most frequently reported thresholds were 10 µmol/L at 24 hours (42%), 1 µmol/L at 48 hours (44%), and 0.1 µmol/L at 72 hours (55%). The threshold values varied widely at 24, 48, and 72 hours by 750-, 100-, and 3-folds, respectively. For most of the studies (87%), time measurement was initiated at the start of infusion. Majority of studies (81%) used immunoassays to quantify methotrexate, whereas 19% used liquid chromatography, with no significant difference in concentration thresholds observed between assay types.

Conclusions: Significant variability exists in the thresholds used to define delayed HDMTX elimination, particularly at 48 hours, with the differences not explained by assay method. These inconsistencies affect clinical decisions, including toxicity predictions and rescue therapy implementation. Although standardization is needed to improve comparability, threshold definitions should also reflect population-specific pharmacokinetics and toxicity profiles to support more precise HDMTX monitoring and outcomes.

Objectives: The aims were to investigate the presence of pyrethroid metabolites (MetaPyr) in the urine of mothers and their premature newborns, and assess potential transplacental transmission and the evolution of these compounds in the early days of life.

Methods: In this prospective study, the first urine samples were collected from 63 premature infants and 55 mothers (<34 weeks' gestation) between Sept 2021 and Oct 2022. The MetaPyr concentrations were determined using liquid chromatography-tandem mass spectrometry.

Results: At least 1 MetaPyr was detected in the urine of 98.2% of mothers. At least 1 MetaPyr was detected within the first 3 days of life in 70% of newborns. The most frequently detected metabolites in the newborns were trans-DCCA and DBCA. Metabolites detected in newborns are generally present in maternal samples. Longitudinal urine analysis of 47 premature infants showed variable MetaPyr trends over time. Notably, FPBA was present in some infants but absent in all maternal urine samples, appearing from day 8 onward.

Discussion: The results emphasized the maternal-fetal transmission of MetaPyr and the complexity of its metabolism and excretion in early life. The detection of these biomarkers in the first urine samples of 80% of preterm neonates may be explained by 2 hypotheses: (1) direct maternal-fetal transmission of MetaPyr through maternal blood, as the mother may have been exposed during pregnancy, and (2) transfer of parent pyrethroids to the fetus, followed by fetal metabolism and urinary excretion.

Conclusions: This pilot study suggested prenatal exposure to pyrethroids in premature newborns, highlighting the need to monitor pesticide exposure from birth, particularly in vulnerable populations. This phenomenon, described as "exposure capital at birth," occurs before any environmental contact. This is followed by uninterrupted environmental exposure during the first days of life.

Purpose: Given its widespread availability, paracetamol (acetaminophen and p-aminophenol) is frequently ingested in overdose, making paracetamol poisoning one of the most common drug-induced poisonings worldwide.

Methods: A comprehensive overview of recent developments in the treatment of acute paracetamol poisoning is presented, with the aim of improving clinicians' understanding of the diagnosis and treatment of patients with paracetamol poisoning.

Results: Paracetamol's pharmacokinetics and toxicokinetics are examined, along with its toxicity (doses and early concentrations); massive overdose or high-risk ingestion; treatment of specific populations such as children, pregnant women, and patients with obesity; prognostic markers of paracetamol toxicity; gastrointestinal decontamination; renal replacement therapy; antidotal therapy with acetylcysteine dosing regimens; adverse reactions; and acetylcysteine alternatives or adjunctive therapies.

Conclusions: Although paracetamol poisoning seems straightforward in terms of risk assessment and treatment, the developments in its diagnosis and treatment reveal that this field is constantly evolving. Multiple factors must be considered in patients with paracetamol poisoning, making its treatment challenging. This comprehensive overview aims to address these challenges.

Background: Model-informed therapeutic drug monitoring (TDM) optimizes drug-dosing regimens using concentration measurements and mathematical models. Despite its importance, the implementation of TDM and pharmacokinetic (PK) target attainment rates may vary across drug and clinical settings. This study assessed TDM implementation and PK target attainment rates at Seoul National University Hospital using electronic medical records.

Methods: Patient data for 24 drugs with established in-house concentration tests and at least 1 concentration measurement between January 2015 and December 2023 were extracted from a clinical data warehouse. Clinical covariates, including age, height, weight, and serum creatinine and albumin levels, were matched to the concentration data. Model-informed TDM use was indirectly calculated based on the number of patients and tests with TDM consultation orders because consultations relied entirely on a PK model. A generalized linear mixed-effects model was used to evaluate the association between TDM consultations and PK target attainment rates.

Results: A total of 44,474 eligible patients were identified after excluding 7 patients with duplicate records. The proportion of patients receiving TDM consultations varied by drug, with vancomycin (100%), digoxin (70%), and theophylline (59%) having the highest proportions. For most drugs, the PK target attainment rates were significantly higher with TDM consultation, but for carbamazepine and lithium, they were lower. PK target attainment was lower in patients with decreased renal function, a higher body mass index, or older age.

Conclusions: The use of model-informed TDM, measured as the proportion of TDM consultations, varied across drugs and was generally associated with higher PK target attainment rates. Renal impairment, obesity, and advanced age require specific considerations to determine optimal dosing.

Background: Broad-spectrum drug testing is useful in various practical settings, especially when patients present with unknown exposures. Although national poison control data inform trends in toxicity and poison control calls, a need exists for clinical drug detection data across different patient populations.

Methods: To address this need, this retrospective study analyzed drug positivity rates from plasma and urine samples tested on a 127-analyte broad-spectrum drug panel. Samples were stratified by sex and age groups (pediatric <18 years, adult ≥18 years). Positivity rates for drug classes and copositivity patterns were compared using χ2 testing with Bonferroni correction.

Results: In total, 7750 samples (3140 plasma and 4610 urine) were analyzed. Positivity for at least one of the tested analytes was high (86% in plasma and 82% in urine). In urine, significant differences in positivity rates between male and female patients were observed for anticonvulsants, antidepressants, antihistamines, benzodiazepines, muscle relaxants, and nicotine. All substances were more prevalent in female patients, except nicotine. Copositivity was more common in female patients, who were more likely than male patients to test positive for 2 or more drug classes. Pediatrics were more likely than adults to test positive for sedatives but less likely for most other drug classes. Overall, patterns of drug class detection differed significantly by age and sex.

Conclusions: This retrospective study reports real-world positivity patterns in a broad-spectrum drug panel, including significant sex- and age-based differences. The higher rates of copositivity in female patients and the higher prevalence of sedatives in pediatric patients are clinically relevant for interpreting drug screen results and managing acute toxidromes. These findings may be useful to both acute care decision making and public health policy interventions, particularly in the pediatric setting.

Background: The narrow therapeutic window and high pharmacokinetic (PK) variability of vancomycin may lead to trough concentrations outside the usual therapeutic range, requiring dose adjustments. In this study, we aimed to identify suitable pediatric vancomycin models, evaluate their predictive performance, and develop an RShiny-based multimodel informed precision-dosing (multi-MIPD) tool.

Methods: A systematic literature search was undertaken to identify pediatric vancomycin PK models, which were graded according to published quality-assessment criteria. Retrospective vancomycin therapeutic drug monitoring data were used to evaluate the performance of high-quality models. Consensus models (mean, median, and weighted) were constructed. In addition, a MIPD tool was developed using the free R package Shiny and validated for both initial dosing and dose adjustment. This tool was evaluated using a prospective dataset.

Results: Nine models demonstrated excellent predictive performance in the retrospective data set (311 concentrations from 192 patients), with root-mean-square error values ranging from 1.00 to 1.97 mg/L and median individual prediction errors from -0.46 to 0.42 mg/L. The multi-MIPD tool incorporating 9 models is presented in the Supplemental Digital Content 1 (see Appendix, http://links.lww.com/TDM/A894). The optimal model achieved a median individual prediction errors of 0.02 mg/L, and an root-mean-square error of 0.12 mg/L in the prospective data set (42 concentrations from 35 patients). The mean consensus model significantly improved target area under the curve attainment compared with empirical dosing, with 68.73% versus 36.53% for initial dosing and 55.56% versus 22.22% after dose adjustments.

Conclusions: The multi-MIPD tool provided accurate concentration predictions and, compared with empirical dosing, significantly improved vancomycin target attainment, offering a more effective and individualized dosing strategy for pediatric patients.