Therapeutic Drug Monitoring最新文献

Background: This scoping review evaluates the economic impact of therapeutic drug monitoring (TDM) and model-informed precision dosing (MIPD), incorporating clinical pharmacokinetics principles in pediatric populations.

Methods: This study followed the PRISMA-ScR guidelines. From 1057 articles identified, 8 met inclusion criteria (5 retrospective studies and 3 Markov-based simulations) focusing on the following drugs: PEG-asparaginase, valproic acid, carbamazepine, phenytoin, phenobarbital, vancomycin, adalimumab, tobramycin, cyclosporine, and perampanel.

Results: Most studies reported cost savings or improved cost-effectiveness with TDM-MIPD strategies. However, analyses were limited to direct medical costs, with little consideration of indirect or societal costs. Also, methodological heterogeneity limited direct comparisons.

Conclusions: The lack of standardized methodologies and economic endpoints, along with potential underreporting of negative findings, restricts the generalizability of conclusions. Nevertheless, current evidence supports TDM-MIPD as a potentially cost-effective approach in pediatric pharmacotherapy.

Background: Dried blood spot (DBS) sampling offers several advantages for therapeutic drug monitoring, including minimal invasiveness, low blood volume requirements, and potential for home sampling. However, obtaining spots of sufficient quality for reliable analysis remains a key challenge of DBS. This study aimed to evaluate the impact of enhanced visual and textual guidance on the quality of DBS by analyzing data from a prospective multicenter study involving children and adolescents.

Methods: In total, 108 DBS cards from 56 children were assessed for spot quality. Rejection criteria included spot diameter <6 mm, smeared or irregularly shaped spots, and overlapping spots. Approval and rejection rates, overall success rates of DBS cards, and the most common rejection reasons were compared between the groups that did and did not receive the enhanced visual and textual support (intervention).

Results: Pre-intervention: 47.6% of the DBS cards contained at least 1 spot qualitatively acceptable for analysis, and 25.7% of all spots qualified for analysis. Post-intervention: the acceptance rates increased to 86.6% and 64.3%, respectively. In both the pre- and post-intervention groups, the most common reason for rejection was the presence of smeared or irregularly shaped spots.

Conclusions: Continued improvements in DBS quality rely on effectively addressing challenges associated with home sampling challenges, which is critical for the seamless incorporation of DBS into clinical practice.

Background: Clozapine is the preferred medication for treatment-resistant schizophrenia with therapeutic drug monitoring (TDM) suggested to mediate its safe and effective use. However, clozapine TDM is not a ubiquitous element of care in clinical practice. Understanding the current state of clinicians' perceptions of and barriers to clozapine TDM is a crucial step in improving its use.

Methods: A survey related to the use, perceptions, and barriers of clozapine TDM was distributed across multiple national organizations in the United States, representing several disciplines.

Results: Most of the 190 respondents were consultants or attending physicians (42.5%) or pharmacists (52.3%). Nearly 80% of respondents had ordered clozapine level measurements in the year before completing the survey but identified slow turnaround time (TaT) as an important barrier; 73.5% of respondents noted that level measurements were performed at an offsite laboratory. Although 86.8% agreed that clozapine levels should be checked once an initial target dose was reached, less than half would subsequently order clozapine level measurements routinely, unless clinical factors such as nonadherence (96.5% agreement), new interaction (94.5% agreement), or change in smoking status (94.5% agreement) occurred. More pharmacists than prescribers indicated confidence in interpreting and clinically applying clozapine TDM results (84.6% versus 70.1%, P = 0.024), with a similar finding between the groups regarding faster clozapine TDM TaT, resulting in improved patient safety (89.0% versus 68.7% agreement, P = 0.003). In addition, more pharmacists would also conduct clozapine TDM in the setting of an acute inflammatory or infectious process (84.9% versus 61.2%, P = 0.002).

Conclusions: These data provide insights into clozapine TDM perception, availability, TaT, and barriers. Further research is required to assess whether a faster TaT and more frequent clozapine TDM positively influence patient outcomes from a safety and effectiveness perspective.

Background: Tacrolimus-induced nephrotoxicity is a common adverse effect after liver transplantation. In this study, we aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model to evaluate the relationships among tacrolimus dose, instantaneous and cumulative exposure, and kidney injury.

Methods: Data from adult liver transplant recipients with a once-daily tacrolimus formulation were retrospectively analyzed. A sequential population PK/PD modeling approach using nonlinear mixed-effects modeling was applied. Exposure metrics included trough concentrations, the area under the concentration-time curve [area under the curve (AUC)] over a 24-hour (AUC0-24h) period, and cumulative AUC (cAUC) over 1-6 months. Renal function was defined as the change in estimated glomerular filtration rate (eGFR). Demographics, biochemical parameters, and concomitant medications were evaluated as covariates.

Results: Tacrolimus trough concentrations and eGFR measurements were obtained from a total of 44 patients for 3360 and 3504 measurements, respectively. Tacrolimus PK was best described by a one-compartment model with additive interindividual variability. Clearance was influenced by hematocrit (HCT) and postoperative days (PODs) within the first 14 days. Among exposure metrics, only cAUC over 3 months was significantly associated with renal function decline and provided the best model fit. The final PK/PD model was a direct linear model, with baseline eGFR identified as a covariate on the slope, reflecting individual susceptibility to tacrolimus-associated renal changes.

Conclusions: Cumulative tacrolimus exposure over 3 months is a key determinant of nephrotoxicity and a valuable predictor for dose individualization. Our findings suggest that early PODs, HCT, and baseline renal function should be considered when optimizing tacrolimus therapy.

Purpose: Traditional herbal medicines are crucial in the health care system worldwide, particularly for individuals with chronic illnesses. These remedies are commonly classified by purpose, composition, mechanism of action, and origin, with the World Health Organization outlining 4 main categories: indigenous herbal medicines, those used in traditional systems, modified herbal medicines, and imported herbal products. The authors explored the toxicology of commonly used herbal remedies, including their mechanisms, signs and symptoms of toxicity, and treatment strategies.

Methods: Literature was searched using different published resources and databases, PubMed and ScienceDirect. The searched terms included "herbal medicine," "herbal remedies," "traditional medicine systems," "herbal toxicity," "herbal toxicity mechanism of action/toxicity," among others. The searches were limited to the English language, with no restrictions on publication date.

Results: The perception that herbal medicines are inherently safe is misleading. Herbal remedies can be toxic due to the plant's intrinsic properties or through contamination and adulteration. Moreover, 15%-20% of individuals on prescription drugs concurrently use herbal supplements, increasing the risk of harmful interactions. Incidence of herb-induced toxicities, particularly hepatotoxicity, is related to the use of Kava, Chaparral, Comfrey, Germander, and green tea extract. Moreover, cardiovascular toxicity due to Chan Su and oleander-containing herbal remedy use is detected by assessing serum digoxin concentration and is treated with Digibind. Although advances in modern formulations and increased regulatory oversight have improved safety, shortcomings remain, particularly in public awareness and standardized regulations.

Conclusions: Comprehensive clinical management, patient education, and integration of traditional medicine into mainstream health care ensures safe, effective, and responsible use of herbal products.

Background: Endocrine-disrupting chemicals (EDCs), such as bisphenols and parabens, are widely used in consumer products and can interfere with placental development. Although their cellular and molecular effects have been explored, the relationship between these factors and placental anatomical abnormalities remains unclear. This pilot study assessed histopathological lesions in human placentas and evaluated potential associations with varying bisphenol and paraben concentrations measured in placental tissue.

Methods: Thirty-seven placentas from the Pregnancy Prevention Endocrine Disruptors cohort were analyzed. Histological assessments were conducted according to standardized protocols, which included evaluating chronic villitis of unknown etiology, intervillitis, chorangiosis, and placental trophicity. Bisphenols (bisphenol A, bisphenol S, bisphenol F, and chlorinated bisphenol A derivatives) and parabens (methyl-, ethyl-, propyl-, and butyl-paraben) were assessed using liquid chromatography coupled to tandem mass spectrometry.

Results: EDCs were frequently detected in placental tissue. Villitis of unknown etiology lesions were identified in 16% of placentas; however, high-grade forms were rare. Chorangiosis was observed in 36% of placentas, and 38% showed hypertrophy. No significant associations were observed between EDCs and specific placental lesions; however, these trends may represent an exploratory signal that warrants further investigation.

Conclusions: This study confirms widespread maternal exposure to EDCs and demonstrates the feasibility of directly detecting these compounds in placental tissue. Although no conclusive association was found between EDC exposure and placental lesions, further research with larger cohorts is warranted to explore potential mechanistic relationships.

Background: The clinical diagnosis of heavy metal toxicity presents a formidable challenge, largely because of symptomatology, which is notoriously nonspecific and capable of mimicking a wide array of common medical conditions. The current diagnostic paradigm, which relies on measuring a single metal in response to specific clinical suspicion, is often inadequate. This approach fails to account for the complex, interconnected nature of the human metallome, in which the toxicity of 1 element is profoundly influenced by the status of others. Antagonistic and synergistic interactions between toxic and essential metals are fundamental to the pathophysiology of toxicity and are largely ignored in single-analyte testing.

Methods: This narrative review argues for a paradigm shift from targeted measurements to comprehensive quantitative screening.

Results: We delineated the diagnostic difficulties due to nonspecific symptoms and how existing clinical guidelines focus on single-element action levels. We then present an intricate web of metal-metal interactions that render the current approach insufficient. The cornerstone of this argument is the maturation of analytical technology. Inductively coupled plasma tandem mass spectrometry (ICP-MS/MS) has overcome the longstanding challenge of atomic and polyatomic interference in complex biological matrices owing to its high selectivity, enabling the development of robust, validated, and high-throughput multielement panels.

Conclusions: By providing a holistic view of an individual's elemental profile, the metallomic footprint of their exposome, this approach offers a more complete and clinically relevant picture, capturing not only the toxicant but also the biological context in which it acts. We conclude that quantitative multielement screening is no longer a theoretical possibility but a practical necessity for clinical toxicology to enhance diagnostic accuracy and improve patient outcomes.

Background: Tacrolimus is the most commonly used immunosuppressant drug in solid organ transplant recipients. Different formulations of tacrolimus have distinct pharmacokinetic profiles due to differences in absorption and elimination. This study aimed to investigate the influence of CYP3A5 polymorphisms on tacrolimus exposure after conversion from immediate-release tacrolimus (Tac-IR) to prolonged-release tacrolimus (Tac-LCP) in stable kidney transplant recipients.

Methods: Intensive pharmacokinetic sampling was performed in 19 kidney transplant recipients before and 1 month after switching from Tac-IR to Tac-LCP. Patients were genotyped for CYP3A5 polymorphisms.

Results: Patients expressing CYP3A5*1 required a significantly higher dose of Tac-IR than nonexpressers to achieve similar predose concentrations (C0), maximum concentrations (Cmax), and area-under-the-curve values (AUC0-24h). After switching to Tac-LCP, CYP3A5*1 expressers had similar C0 values but significantly higher Cmax and AUC0-24h values compared with nonexpressers. Dose-normalized exposure showed that CYP3A5*1 expressers had a lower conversion rate than nonexpressers (0.58 versus 0.807).

Conclusions: These results suggest that CYP3A5 genotype should be considered when adjusting the tacrolimus dose during conversion from Tac-IR to Tac-LCP. C0 values may not adequately reflect the higher exposure observed in CYP3A5*1 expressers, highlighting the importance of AUC0-24h in guiding dose adjustment.

Abstract: Cortisol deposited in the hair can be used as a tool for the objective assessment of chronic stress. The authors compared the efficiency of cortisol extraction by several methods in different individuals. Hair samples from 20 men were either prewashed or not, and either cut into small pieces with scissors or pulverized using liquid nitrogen. Afterward, temperature (16 hours at 52°C), sonication (2 hours), or both were used to increase the efficiency of methanol extraction. Duplicate samples were analyzed using enzyme-linked immunosorbent assay for cortisol measurement (n = 480). Cortisol data had a non-normal distribution and are expressed as median. An alpha level less than 0.05 was considered significant. Hair cortisol levels were between 0.3 and 60 pg/mg and differed between the participants (P < 0.001). No significant difference was noted between prewashing and not prewashing procedures (19.5 vs. 20.6, respectively; P = 0.247). Cutting into small pieces with scissors yielded lower cortisol levels compared with pulverization (17.4 vs. 22.0 pg/mg, P = 0.002); however, no differences were observed when temperature or sonication or both were used (20.2, 19.7, and 19.6 pg/mg, respectively, P = 0.971). Overall, the technique was sensitive to detect varying levels of hair cortisol in each individual. Prewashing, temperature, and sonication were observed to be unnecessary. Although pulverization caused higher hair cortisol extraction (4.6 pg/mg), it was relatively low compared with the large interindividual differences. Thus, any of the methods could be used, especially when the time and cost of analyses are considered.