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BACKGROUND: There is no guideline regarding whether patients treated with intravenous corticosteroids for acute severe ulcerative colitis (ASUC) should be monitored in the hospital after transitioning to oral steroids. Our study aimed to: (1) compare rates of oral steroid transition failure and 30-day readmission between ASUC hospitalizations with extended inpatient monitoring compared to accelerated inpatient monitoring, and (2) identify predictors of oral steroid transition failure. METHODS: A retrospective cohort study of ulcerative colitis (UC) related admissions at UCSF from 2014 to 2022 was conducted comparing rates of steroid transition failures in extended inpatient monitoring (≥ 24 h on oral steroids prior to discharge) to accelerated inpatient monitoring (

The rise in global obesity prevalence has increased the need to understand the pharmacokinetics of drugs in overweight and obese individuals. Tuberculosis remains a significant health challenge, and its treatment outcomes can be influenced by the pharmacokinetic profiles of antitubercular agents. This literature review aims to point out the clinical pharmacokinetics of antitubercular drugs in the overweight and obese patient population, highlighting considerations for potential dosage adjustments. We conducted a comprehensive search of the PubMed US National Library of Medicine from inception to January 2024. Articles focusing on the pharmacokinetics of antitubercular agents used for both drug-susceptible and multidrug-resistant tuberculosis in overweight and obese adults were included. In total, 349 scientific articles were identified and examined for human pharmacokinetic parameters. Of these, 19 were included in this article. To highlight potential differences, pharmacokinetic data for normal-weight tuberculosis patients are also presented, albeit selectively. In general, pharmacokinetic studies of antitubercular agents in overweight and obese individuals are lacking. Fixed-dose combinations often used in the treatment of drug-susceptible tuberculosis are not recommended when treating these population groups. Rather, individual dosing based on therapeutic drug monitoring and the known solubility of the substance should be considered. To improve the management of tuberculosis in overweight and obese patients, there is an urgent need for pharmacokinetic studies and, ultimately, adequate dosing in this patient population, especially given the increasing prevalence of obesity. [ABSTRACT FROM AUTHOR]

Bruton's tyrosine kinase inhibitors (BTKis) exhibit significant interindividual pharmacokinetics, making therapeutic drug monitoring (TDM) a promising approach for personalized therapy. However, simultaneous quantification of multiple BTKis poses technical challenges. A unified protocol for BTKis detection would be clinically desirable. Herein, we developed and validated a novel LC-MS/MS method for the simultaneous analysis of four BTKis including ibrutinib (IBR), zanubrutinib (ZAN), orelabrutinib (ORE), and acalabrutinib (ACB) and active metabolite of IBR and ACB (DIH and ACBM, respectively) in human plasma. The samples were prepared by liquid-liquid extraction using tert-butyl methyl ether. Ibrutinb-d4 (IS) was used as an internal standard. Chromatographic separation was obtained on an XBridge C18 column and connected to an LC-30AD system coupled to an API 4000+ mass spectrometer. The mobile phase comprised 10 mM ammonium acetate containing 0.1% formic acid and acetonitrile containing 0.1% formic acid. The optimized multiple reaction monitoring transitions of m/z 441.4 → 138.3, 475.4 → 304.2, 472.5 → 455.5, 428.3 → 411.5, 466.1 → 372.2, 482.2 → 388.4, and 445.5 → 142.5 were selected to inspect IBR, DIH, ZAN, ORE, ACB, ACBM, and IS, respectively. The method exhibited linearity from 1 to 1000 ng/mL (r > 0.99) for all analytes, with intra-day and inter-day precision of 1.8 to 9.7% and accuracy below 15%. Recovery ranged from 90.4 to 113.6%, and matrix effect varied from 89.3 to 111.0%. All compounds demonstrated stability under relevant conditions. Application of the method to 57 blood samples from 18 patients demonstrated high interpatient variability, with ORE plasma concentrations ranging from 25.6 to 89.9%. The validated LC-MS/MS method provides a feasible, specific, and rapid approach for quantification of BTKis in clinical settings. Simultaneous determination of four BTKis and their metabolites in a single extraction process and chromatographic run reduces analysis time, cost, and resources. The observed variability among individuals highlights the value of TDM for personalized treatment. [ABSTRACT FROM AUTHOR]

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are associated with high mortality rates. Optimal antibiotic dosage plays a crucial role in reducing MRSA burden; thus, the use of therapeutic drug monitoring (TDM) in the clinical practice, especially of new drugs such as ceftobiprole, ceftaroline, dalbavancin, and oritavancin, should be implemented. We aim to examine and summarize the available evidence about TDM of anti-MRSA molecules, with a focus on pneumonia, endocarditis and vascular infections, and bone and joint infections. We applied 'therapeutic drug monitoring' and ' Staphylococcus aureus ' as search terms in PubMed, considering a time frame of 24 years (2001–2024). Articles in English language, non-duplicated, evaluating antibiotic therapeutic target, and role of TDM were included in the study. In this review, available data for therapeutic target and TDM were critically analysed and summarized and suggestions about the use of old and new anti-MRSA antibiotics were provided, focusing on optimal dosages, tissue penetration according to infection types, and toxicity. Limitations to the widespread use of TDM in clinical practice were discussed. The use of TDM may play an important role for the optimal management of patients with MRSA infections and may impact on patient outcomes by increasing efficacy and reducing the risk of adverse events. TDM may be implemented in clinical practice; however, several limitations such as the wide variability in the methodology and the need for skilled personnel need to be considered. [ABSTRACT FROM AUTHOR]

The letter to the editor discusses the use of Isavuconazole in treating invasive fungal disease (IFD) in pediatric hematology and oncology patients undergoing chemotherapy or cellular therapy. Isavuconazole is a pro-drug rapidly converted to an active drug that inhibits fungal enzyme synthesis. It is approved for invasive aspergillosis and mucormycosis in adults and shows promise in pediatric patients. A study in Poland analyzed Isavuconazole use in children with malignancy, hematopoietic cell transplantation, or CAR-T therapy, showing effectiveness in treating IFD, especially in pediatric hematology and oncology settings. [Extracted from the article]

For fixed-duration therapies against chronic lymphocytic leukemia (CLL), undetectable measurable residual disease (MRD) predicts overall and progression-free survival more accurately than complete remission. For indefinite therapies, MRD status can direct discontinuation of treatment. We systematically reviewed the relationship between antineoplastic drug exposures and undetectable MRD in CLL. Seventeen trials from MEDLINE and EMBASE met the inclusion criteria; four of which evaluated drug exposures in relation to MRD status. Undetectable MRD was associated with higher trough concentrations of ofatumumab and alemtuzumab, as well as increased maximum concentration and area under the plasma concentration curve (AUC) of ibrutinib. One study found an association between high rituximab AUC and undetectable MRD until adjusting for tumor burden. The limited studies, lack of exposure measurements of concomitant drugs, and high heterogeneity in designs limit the results' generalizability. Further research is needed to explore the exposure–MRD relationship and the possibility for therapeutic drug monitoring in CLL. [ABSTRACT FROM AUTHOR]

The branch of biomimetics has witnessed a profound impact on the field of biosensor technology, reflected in sustainable analyte detection. A vast array of biosensor platforms with improved/upgraded performance have been developed and reported. No wonder the motivation from the field of biomimetics has a huge impact on generating detection systems with escalated degrees of manipulation and tunability at different levels. More recently, biomimetic biosensor technology has found potential in constructing bio-inspired materials such as aptamers, MIPs, nanozymes, DNAzymes, Synzymes, etc. to be integrated with biosensor fabrication. The establishment of a sensing setup is not limited to the bioreceptor fabrication; the construction of transducing element using biomimetic material have been reported too. Moreover, to serve a biosensing of target analyte from a fatal diseased sample different biomimetic architectures can be designed that mimic in-vivo microenvironmental surroundings to get an exact microenvironment equivalent to natural conditions leading towards designing of a precise treatment strategy. This research area is ever-evolving as there is a scope for upgradation and refinement due to advancing technologies including nanotechnology, biomimetic nanomaterials, microfluidics, optical sensors, etc. This review is an attempt to comprehend and juxtapose the very primary innovations in the field of biomimetic biosensor technology to realize its comprehensive and wide-range scope and possibilities. [Display omitted] • This review is an attempt to realize the significance of biomimetics in fabrication of a biosensing platform/device. • Several biomimetic materials like aptamers, MIPs, nanozymes, etc. have been discussed in detail to shade light on the amalgamation of various fields. • Mimicking various biomacromolecules like nucleic acids and enzymes aids in sustainable analyte detection. • Apart from biomimetic materials, naturally inspire biomimetic platform such as organ-on-chip and tissue engineering have also been reported. • Biomimetic biosensors in healthcare applications like oxygen level monitoring and monitoring the delivery of drug molecules are also reported. [ABSTRACT FROM AUTHOR]

Background: Impaired impulse control is often seen in Parkinson's disease (PD) patients using dopamine agonists. Methods: We performed a therapeutic drug monitoring study of 100 PD patients using ropinirole or pramipexole extended release. Three blood samples were collected on the same day. Serum concentrations were measured, and 24 h area under the curve (AUC) calculated. The validated Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) was used for assessing impulse control. Results: Total ropinirole drug exposure showed weak, but significant correlation to the QUIP-RS score. No correlation between pramipexole serum concentrations and QUIP-RS was found. In ropinirole patients, both agonist dose and total dopaminergic treatment were correlated with QUIP-RS. Duration of ropinirole treatment correlated with impaired impulse control, and duration of dopaminergic treatment of any type correlated with QUIP-RS scores in both ropinirole and pramipexole patients. Conclusions: Our main finding is that impaired impulse control is correlated to both total drug exposure (AUC) and dopamine agonist dose for ropinirole, but not for pramipexole. These observations indicate that different strategies may be useful for treating PD patients with impaired impulse control: ropinirole dose reduction could be beneficial, whereas pramipexole treatment may have to be stopped. [ABSTRACT FROM AUTHOR]

Background: Current guidelines recommend dosing vancomycin based on the area under the concentration time curve (AUC) to maximise efficacy and minimise the risk of nephrotoxicity. The preferred approach to AUC-guided therapy is to apply model-informed precision dosing (MIPD). However, the adoption in clinical practice has been slow. Aim: We aimed to develop an intervention, including a standardised MIPD workflow and an implementation plan for vancomycin AUC-guided dosing, in a Swedish tertiary hospital. Method: The intervention was developed in a framework-guided process. The design phase included stakeholder feedback (nurses, pharmacists, physicians), local data collection and feasibility testing of intervention components with parallel consideration of implementation aspects. The hypothesised relationships between the different components, implementation strategies and the mechanism of action resulting in expected outcomes were represented by a logic model. Results: The final intervention consisted of a workflow for MIPD, with defined roles and responsibilities, as well as processes for data and information transfer. Details were provided in supportive documents; an instruction on therapeutic drug monitoring (TDM) sampling and documentation for nurses, and a detailed dosing software instruction for MIPD consultants and clinical pharmacists. Activities to facilitate implementation included the development of a local clinical routine for vancomycin dosing, staff training and recurring MIPD rounds. Conclusion: An intervention for MIPD, with an implementation plan for AUC-guided dosing of vancomycin, was developed for a tertiary hospital setting. The process can be used as guidance for other institutions with similar context wishing to initiate MIPD. [ABSTRACT FROM AUTHOR]

Background: The optimal pharmacokinetic and pharmacodynamic (PK/PD) parameters of vancomycin that can improve outcomes in enterococcal infections remain controversial. To clarify the therapeutic target for this antibiotic, this study aimed to determine vancomycin PK/PD parameters associated with efficacy in the early (during 72 h) or later (after 72 h) phase of treatment and nephrotoxicity in enterococcal bloodstream infection patients. Methods: This multicenter retrospective study reviewed medical records of patients with enterococcal bloodstream infections treated with intravenous vancomycin infusion for at least 72 h between January 2016 and March 2024 at Phramongkutklao Hospital or Nopparatrajathanee Hospital in Bangkok, and Rachaburi Hospital in Rachaburi Province, Thailand. Patients with data available on serum vancomycin concentration were analyzed. The primary outcomes were 30-day mortality and acute kidney injury. The estimates of the mean 24-h area under the curve in the first 72 h (AUC24) and in steady state (AUCss) were determined by Bayesian theorem. Results: Overall, 201 vancomycin concentrations were measured within the first 72 h after vancomycin treatment, while 156 were in a steady state (> 72 h). According to Classification and Regression Tree analysis, vancomycin AUC at 420 mg·h/l was the PK/PD target for 30-day mortality. Results reveal that patients with AUC24 (early phase) and AUCss < 420 mg·h/l (later phase) had significantly higher 14-day, 30-day, and in-hospital mortality than AUC ≥ 420 mg·h/l groups. In addition, patients with AUC24 ≥ 420 mg·h/l in the early phase had significantly reduced microbiological failure (p = 0.004). Patients with AUC ≥ 700 mg·h/l in early and later phases had significantly increased acute kidney injury risk. In addition, patients receiving concomitant nephrotoxic drugs had an AUC cutoff value of 650 mg·h/l. Multivariate Cox regression analysis showed that vancomycin AUCss < 420 mg·h/l, unknown source of bacteremia, and acute kidney injury were significantly associated with 30-day mortality. Conclusions: AUC 420–650 mg·h/l in early and later phases was the target of vancomycin's PK/PD in enterococcal bacteremia patients for efficacy and to prevent acute kidney injury. This study suggests close monitoring of vancomycin levels to ensure efficacy and safety. [ABSTRACT FROM AUTHOR]

Background: Therapeutic drug monitoring is an integral part of organ transplantation. A rapid, simple, economical, and robust high‐performance liquid chromatography‐tandem mass spectrometry (HPLC‐MS/MS) method for simultaneously determining the immunosuppressants cyclosporine A and tacrolimus might increase detection efficiency. Methods: In this study, we developed and validated a rapid HPLC‐MS/MS method. Whole blood samples of 100 μL were prepared by protein precipitation with acetonitrile and 0.5 mol. L−1 ZnSO4. Chromatography was performed on a pre‐column using a gradient elution with 20 mmol. L−1 ammonium formate and 0.1% (v/v) formic acid in water (mobile phase A) and 0.1% (v/v) formic acid in methanol (mobile phase B) at a flow rate of 1.5 mL.min−1. The analysis time was 2.2 min. Electrospray ionization and multiple reaction monitoring were performed. The lower limit of quantification was set at 1 ng. L−1 for tacrolimus and 50 ng. L−1 for cyclosporine A. Results: The method showed adequate accuracy and precision with a sufficient linear range. The calibration curve range of tacrolimus and cyclosporine A was 1–30 and 50–1500 ng·mL‐1, respectively. All correlation coefficients were >0.99. Conclusions: The developed HPLC‐MS/MS is rapid and can be used for simultaneous monitoring of tacrolimus and cyclosporine A. [ABSTRACT FROM AUTHOR]

Background: Toxic epidermal necrolysis (TEN), a severe cutaneous hypersensitivity reaction induced particularly by drugs, is diagnosed when there is a fever of ≥ 38 °C, mucocutaneous symptoms, a rash with multiple erythema, and skin peeling of ≥ 30% of the body surface area. The mortality rate of TEN is high, and thrombocytopenia during treatment can lead to severe outcomes. Intravenous immunoglobulin (IVIg) is used when steroids are ineffective in TEN and may improve mortality; however, thrombocytopenia is a rare adverse event associated with IVIg use. We report the case of thrombocytopenia during IVIg therapy for TEN. We also reviewed previous reports to learn more about the clinical course and mechanism of IVIg-induced thrombocytopenia. Case presentation: An 83-year-old man with end-stage renal failure on hemodialysis was diagnosed with TEN. After an inadequate response to pulse methylprednisolone therapy, IVIg (400 mg/kg/day) was administered for 5 days. He developed thrombocytopenia after IVIg administration, leading to the diagnosis of thrombocytopenia due to IVIg after excluding other diseases. The platelet count began to increase approximately 10 days after IVIg administration. Conclusions: When IVIg is administered for TEN, the risk of thrombocytopenia should be recognized and the platelet count should be carefully monitored. [ABSTRACT FROM AUTHOR]

Cytochrome P450 (CYP) 3A4 plays a major role in drug metabolism. Its activity could be determined by non-invasive and cost-effective assays, such as breath analysis, for the personalised monitoring of drug response. For the first time, we identify an isotopically unlabelled CYP3A4 substrate, tolterodine that leads to the formation of a non-toxic volatile metabolite, acetone, which could potentially be applied to monitor CYP3A4 activity in humans. In vitro biotransformation of tolterodine by HepG2 cells overexpressing CYP3A4, CYP2D6 or CYP2C9 was investigated by LC-MS analysis of cell culture supernatant for the non-volatile metabolite, N-dealkylated tolterodine, and PTR-ToF-MS analysis of the headspace for acetone. The highest level of the N-dealkylated metabolite was produced by HepG2-CYP3A4. Concentration dependent effects of tolterodine were analysed, resulting in TC50 values of 414 µM and 375 µM for HepG2-CYP3A4 and reference cells, respectively. Acetone and N-dealkylated tolterodine levels increased continuously over 24 h in HepG2-CYP3A4. Treatment with either a pan-CYP inhibitor, 1-aminobenzotriazole, or a CYP3A4 inhibitor, ketoconazole, considerably reduced the production of both metabolites in HepG2-CYP3A4 cells. These findings pave the way for the further development of non-invasive breath tests using unlabelled precursors to determine CYP enzyme activity in individuals. [ABSTRACT FROM AUTHOR]

The scourge of drug addiction and abuse poses a significant challenge to society. Opioid drugs acting on μ-opioid receptor (OPRM1) make it one of the pivotal targets for drug addiction. In the past decade, sewage analysis has become a prevalent method of drug monitoring. However, traditional methods of detecting drugs in sewage are cumbersome, and rapid detection methods are relatively lacking. To address this, an innovative OPRM1-SNAP-tag/CMC method to directly identify drug components in sewage was established. Cell membrane chromatography (CMC) is an affinity chromatography technique which effectively detects receptor affinity substances. Cells constructed with high expression of specific receptor could be used to screen for compounds acting on the receptor. CMC based on OPRM1 provides a potentially convenient and effective tool for the detection of targeted drug components in sewage. In this study, the selectivity, reproducibility, column lifetime, and carryover of the CMC column had been assessed. Initially, we eluted the collected domestic sewage with methanol and acetonitrile, and the retention peaks were observed on the CMC system. Subsequently, without any preliminary sample preparation, we directly injected filtered samples of suspicious sewage into the OPRM1-SNAP-tag/CMC system, where we observed retention peaks as well. The retained components were further identified as morphine by using UPLC-MS/MS. In conclusion, the OPRM1-SNAP-tag/CMC method stands out as a reliable and robust model for the detection of drug components in sewage. It provides a valuable analytical tool for frontline drug control efforts, enhancing our capacity to monitor and mitigate the impact of drug abuse on society. [ABSTRACT FROM AUTHOR]

Background: Ripretinib, a broad-spectrum tyrosine kinase inhibitor, has been approved for the treatment of advanced gastrointestinal stromal tumors in adult patients. Clinical studies have shown that higher in vivo exposure of ripretinib correlates with improved efficacy, highlighting the potential clinical significance of therapeutic drug monitoring. In this study, a simple and stable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was attempted to be established and validated for pharmacokinetic studies of ripretinib and its metabolite DP-5439 and therapeutic drug monitoring in human plasma. Method: Ripretinib and DP-5439 were separated by chromatography using a Thermofisher Hypersil GOLDTM C18 HPLC column. The mobile phase for gradient elution is composed of 0.1% formic acid in water and acetonitrile. Multiple reaction monitoring was implemented along with electrospray ionization positive mode for detection. The ion pairs of ripretinib, DP-5439 and internal standard D8-ripretinib were m/z 510.1→m/z 417, m/z 496.11→m/z 402.9 and m/z 518.15→m/z 420, respectively. Plasma samples from ripretinib-treated patients of our hospital were collected for pharmacokinetic analysis. Results: Ripretinib and DP-5439 demonstrated a strong linear relationship over 10–5,000 μg/L (R 2 > 0.99). Accuracy, precision, specificity, recoveries, matrix effect, stability, and dilution effect were all validated and found to meet the required criteria. Following validation, the method was utilized to determine plasma samples from patients treated with ripretinib. The median steady-state trough concentrations (Cmin, range) were 398.50 (66.98 ∼ 1,458.91) μg/L for ripretinib and 654.74 (30.71 ∼ 1,522.48) μg/L for DP-5439, with a total median concentration of 1,129.46 (140.95 ∼ 2,981.39) μg/L in patients receiving ripretinib at 150 mg once daily. Meanwhile, using the established methods, the study conducted pharmacokinetics studies on four patients with ripretinib and DP-5439. Conclusion: This study developed and validated a robust LC-MS/MS method for determining ripretinib and its metabolite DP-5439 in human plasma. Furthermore, the practicality of this method in clinical sample analysis was demonstrated. This approach can serve as an effective tool for the pharmacokinetics analysis and therapeutic drug monitoring in patients treated with ripretinib. [ABSTRACT FROM AUTHOR]

Purpose: CytoSorb® (CS) adsorbent is a hemoadsorption filter for extracorporeal blood purification often integrated into continuous kidney replacement therapy (CKRT). It is primarily used in critically ill patients with sepsis and related conditions, including cytokine storms and systemic inflammatory responses. Up to now, there is no evidence nor recommendation for the use of CS filters in sepsis (22). There is limited clinical data on the effect of CS on the plasma concentrations of beta-lactams. We aimed to evaluate the statistical and clinical impact of CS in a post-filter CKRT-CS setting on the plasma concentrations of the antibiotics meropenem and piperacillin in critically ill patients. Methods: Patients admitted to the intensive care unit (ICU) who received a prolonged infusion of piperacillin or meropenem with CS-combined CKRT were included in this retrospective analysis. TDM (therapeutic drug monitoring) plasma blood samples were collected at three different points. The differences in antibiotic concentrations between Pre, Intra, and Post were statistically compared to evaluate the total and isolated contributions of CKRT and CS to antibiotic removal. CS, CKRT and combined clearance (CL) values were calculated. The hypothesis was that the CS filter would have no clinically relevant impact on antibiotic levels. Results: 207 TDM samples were taken from 24 critically ill patients requiring beta-lactam antibiotics. Among these, 129 were meropenem samples, and 78 were piperacillin samples. A decrease in both antibiotic levels was observed between Pre and Intra, and Pre and Post, and the median relative difference between was >15% (meropenem: Pre–Intra 34.8%, Pre–Post 35.8%; piperacillin: Pre–Intra 41.1%, Pre–Post 34.7%), indicating a statistically and clinically significant effect of CKRT on both antibiotic exposures. No significant difference was observed between Intra and Post indicating no clinically relevant drug removal via the CS filter. Changes in CL attributed to CS were minimal, with combined CL differing by ≤8.60% compared to CKRT clearance. Conclusion: The application of CS does not appear to significantly affect plasma concentrations of meropenem and piperacillin in critically ill patients. [ABSTRACT FROM AUTHOR]

Background: Pro re nata (PRN) medication is used "as needed" for symptoms such as agitation and insomnia, in addition to regular daily pharmacotherapy of mental disorders. However, there is no high-quality evidence on the effectiveness of psychotropic PRN medications and concerns have been raised about their potential to contribute to polypharmacy. This study introduced a psychotropic PRN prescription-monitoring programme for psychiatric inpatients with the aim of examining the change before and after the implementation of the programme. Method: This study included 389 patients admitted to the psychiatric department between 1 July 2021 and 30 June 2023. The psychotropic PRN prescription-monitoring programme was implemented in July 2022, and the participants were classified into monitoring and non-monitoring groups. Demographic data (age, sex, and diagnosis), regular prescriptions before admission and at discharge, psychotropic PRN prescriptions before admission and at discharge, and the total number of psychotropic PRN prescriptions during hospitalisation were compared between the two groups. Data on psychotropic prescription were collected by psychotropic category. The significance level of 5% was set at 1.67 × 10−3 using the Bonferroni correction for multiple testing. Results: The psychotropic PRN prescription ratio at discharge in the monitoring group was 9.3%, which was significantly lower than the 28.1% in the non-monitoring group. The percentage of patients with a PRN prescription during hospitalisation in the monitoring group was 29.8%, which was significantly lower than the 64.5% in the non-monitoring group. In the non-monitoring group, there was no statistically significant difference in the number of psychotropic drugs prescribed regularly before and after admission. However, in the monitoring group, the number of psychotropic drugs in the regular prescriptions at discharge was 1.87 ± 1.24, which was significantly lower than 2.47 ± 1.90 in the regular prescription before admission. Conclusions: Our findings suggest that a psychotropic PRN prescription-monitoring programme may contribute to the elimination of polypharmacy, including regular prescriptions. Further research is required to optimise psychotropic PRN prescriptions and reduce polypharmacy. [ABSTRACT FROM AUTHOR]

Background: Polymyxin B sulfate (PBS) and colistin sulfate (CS) are the last-line treatments for infections caused by multidrug-resistant Gram-negative bacteria, but their efficacy and safety have not been validated. The aims of the current study were to (1) determine their efficacy and safety among critically ill patients and the influencing factors, and (2) determine the relationships of drug exposure with efficacy and safety, to provide evidence for the precision dosing. Method: This retrospective study included 100 critically ill patients treated with PBS and 80 treated with CS. The efficacy outcomes were clinical efficacy and 30-day mortality, while the safety indicator was acute kidney injury (AKI) incidence. Result: There was no significant difference between the two drugs in clinical efficacy, 30-day mortality, or overall AKI incidence, but the incidence of stage 3 AKI was significantly higher in the PBS cohort than the CS cohort. Therapeutic drug monitoring (TDM) and trough concentration (Cmin) were significantly associated with clinical efficacy and AKI in both cohorts. Classification and regression tree analysis revealed that Cmin values of ≥0.91 mg/L for PBS and Cmin ≥ 0.53 mg/L for CS were associated with higher clinical efficacy. Conclusion: There is basically no significant difference in the efficacy and safety of PBS and CS. TDM can significantly improve the clinical efficacy of both drugs and reduce the incidence of AKI. TDM is therefore recommended to improve the clinical efficacy while reducing the adverse reactions. [ABSTRACT FROM AUTHOR]

A long history of policymaking and regulation constructed for the purpose of ensuring adequate fetal and infant protections has inadvertently sanctioned the widespread exclusion of pregnant and lactating patients from biomedical research, leaving a paucity of high quality data necessary for clinical decision-making. Although well-intended, the regulatory classification of pregnant women as "vulnerable," in conjunction with burdensome enrollment criteria and other factors weighing against broad inclusion, have ultimately placed the health and safety of these women and their babies in jeopardy. Robust measures are urgently needed to overcome patient and physician reluctance, address substantial evidence gaps, and rectify long-standing disparities which precipitate disproportionately poor health outcomes among this population. In February 2023, the Advancing Safe Medications for Moms and Babies Act of 2023 (the Act) was introduced in the United States House of Representatives with the overarching goal of enabling pregnant and lactating women to achieve equitable participation in clinical research and contribute to developing important biomedical knowledge to guide and improve health care delivered to these patients. This review discusses the historical influence of federal human subject protection regulations on the health and clinical treatment of pregnant and lactating women, outlines and critically analyzes the provisions incorporated into the Act, and reflects on the potential long-term impact the Act would have should it be successful in becoming law. Key Points Pregnant and lactating patients are widely excluded from clinical research. Evidence guiding the treatment of these patients is limited and of unacceptably low quality. Proposed legislation seeks to rectify disparities and empower these patients through improved representation in research. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19), an extremely contagious illness, has posed enormous challenges to healthcare systems around the world. Although the evidence on COVID-19 management is growing, antiviral medication is still the first line of treatment. Therefore, it is critical that effective, safe, and tolerable antivirals be available to treat early COVID-19 and stop its progression. Recently, favipiravir (FAV) has received FDA approval as safe and effective antiviral medication for COVID-19 management. Nitazoxanide (NTZ) also possesses antiviral and immunomodulating activities. Moreover, FAV and NTZ in combination are clinically used in COVID-19 treatment with reported safety, synergistic antiviral and immunomodulating effects. Despite the availability of various clinical studies on both FAV and NTZ, no existing analytical application for the simultaneous estimation of FAV and NTZ exists. As a result, the current work goal is to establish a green HPLC method for their analysis and implementation to human plasma. The developed method utilizes isocratic elution with 0.1% aqueous formic acid: ethanol (55:45, v/v) and dantrolene as internal standard. The bioanalytical validation parameters passed the FDA acceptance criteria. NEMI, eco scale, AGREE and ComplexGAPI approaches were used for qualitative and quantitative evaluation of the method's greenness. [ABSTRACT FROM AUTHOR]

To compare a new ready-to-use monotest immunoassay, CHORUS Promonitor, for the quantification of serum biological drug levels and anti-drug antibodies of anti-TNF agents, against the reference batch-based ELISA test, Promonitor.Blood samples were collected from patients treated with anti-TNF agents, infliximab (IFX) or adalimumab (ADL). IFX and ADL levels, as well as anti-IFX and anti-ADL antibodies were quantified and compared between the standard ELISA reference test, Promonitor, and the automated monotest ELISA assay, CHORUS Promonitor. Data analysis included both qualitative and quantitative comparison between both tests. For the qualitative comparison, overall percent agreement (OPA) was calculated. For the quantitative comparison, Passing-Bablok regression analysis and Bland–Altman analysis were used.For IFX and ADL levels, the qualitative overall agreement between methods was 100 % (Cohen’s coefficient=1). For anti-IFX and anti-ADL antibodies, OPA was 98.8 % and 97.3 %, respectively. Quantitative comparison indicated a very strong correlation between both assays: IFX (r=0.97, n=74), ADL (r=0.95, n=54), anti-IFX (r=0.93, n=72), and anti-ADL (r=0.97, n=61). The regression analysis determined an excellent comparability of drug levels between methods. Bland–Altman analysis showed a bias difference between assays of 6 % for IFX, 0 % for ADL, 24 % for anti-IFX, and 14 % for anti-ADL.Monotest CHORUS Promonitor was a reliable assay to quantify IFX, ADL, anti-IFX and anti-ADL in samples with comparable results to those obtained with the reference batch-based ELISA technique. [ABSTRACT FROM AUTHOR]

Real-time monitoring of therapeutic drugs is crucial for treatment management and pharmacokinetic studies. We present the optimization and affinity tuning of split-aptamer sandwich assay for real-time monitoring of the narrow therapeutic window drug vancomycin, using surface plasmon resonance (SPR). To achieve reversible, label-free sensing of small molecules by SPR, we adapted a vancomycin binding aptamer in a sandwich assay format through the split-aptamer approach. By evaluating multiple split sites within the secondary structure of the original aptamer, we identified position 27 (P27) as optimal for preserving target affinity, ensuring reversibility, and maximizing sensitivity. The assay demonstrated robust performance under physiologically relevant ranges of pH and divalent cations, and the specific ternary complex formation of the aptamer split segments with the analyte was confirmed by circular dichroism spectroscopy. Subsequently, we engineered a series of split-aptamer pairs with increasing complementarity in the stem regions, improving both the affinity and limit of detection up to 10-fold, as compared to the primary P27 pair. The kinetics of the engineered split-aptamer pairs were evaluated, revealing fast association and dissociation rates, confirming improved affinity and detection limits across variants. Most importantly, the reversibility of the assay, essential for real-time monitoring, was maintained in all pairs. Finally, the assay was further validated in complex biological matrices, including the cerebrospinal fluid from dogs and diluted plasma from rats, demonstrating functionality in biological environments and stability exceeding 9 hours. Our study paves the way for applications of split-aptamers in real-time monitoring of small molecules, with potential implications for in vivo therapeutic drug monitoring and pharmacokinetic studies. [ABSTRACT FROM AUTHOR]

The risk of fungal, bacterial, and viral infections is higher in children with hematological and solid malignancies, particularly during periods of profound neutropenia. Although early administration of antimicrobial agents is common, optimizing pharmacological therapy in pediatric patients with cancer is challenging because of their variable pharmacokinetics compared with adults, including differences in body mass and augmented renal clearance, as well as chemotherapy-induced organ toxicity. Therapeutic drug monitoring, which involves measuring drug concentrations in serum or plasma at specific timepoints and adjusting doses accordingly, can be applied to various medications. While standardized targets for all antimicrobial agents in children are lacking, therapeutic drug monitoring appears to be beneficial in preventing serious toxicity and addressing treatment failure or non-compliance. This narrative review aims to analyze current perspectives on therapeutic drug monitoring for antimicrobial drugs in the special population of children with hematological or oncological diseases, including those undergoing hematopoietic cell transplantation. The review provides evidence on the clinical benefits of this method and explores potential future developments in this area. [ABSTRACT FROM AUTHOR]

Background: Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), is actually used to prevent organ transplant rejection and treat metastatic breast, renal, and neuroendocrine cancers. Despite significant pharmacokinetic variability among patients, routine therapeutic drug monitoring (TDM) is not commonly used in oncology. Methods: The aim of this multicenter, prospective observational cohort study is to assess the prevalence of everolimus minimum concentration at a steady state (Cminss) falling outside the therapeutic range (10–26.3 ng/mL) during a routine TDM programme. Sixty patients with metastatic breast, neuroendocrine, or renal cancers, either starting or continuing everolimus treatment according to hospital protocols, are to be included between 1st of January 2024 and 31st of December 2025 (patients undergoing clinical trials are excluded). We hypothesize that 30–50% of our patients and their blood samples will not achieve the target optimal plasma concentrations. Blood samples are collected every 4–6 weeks to monitor drug levels. The secondary goal is to explore correlation between out-of-range everolimus levels and factors such as demographic and anthropometric data, treatment specifics, lab results, genetic polymorphisms, and the presence of toxicity. Conclusions: This study could offer valuable insights into optimizing dosing strategies and may contribute to future research on personalizing everolimus and other anticancer treatments. This personalized approach seeks to tailor therapy not only to the tumour's molecular profile but also to the individual characteristics of each patient, improving both drug selection and dosing precision. [ABSTRACT FROM AUTHOR]

Background/Objectives: Multiple Myeloma (MM) is a hematologic malignancy caused by clonally expanded plasma cells that produce a monoclonal immunoglobulin (M-protein), a personalized biomarker. Recently, we developed an ultra-sensitive mass spectrometry method to quantify minimal residual disease (MS-MRD) by targeting unique M-protein peptides. Therapeutic antibodies (t-Abs), key in MM treatment, often lead to deep and long-lasting responses. However, t-Abs can significantly decrease the total polyclonal immunoglobulin (Ig) levels which require supplemental IgG infusion. Here, we demonstrate the simultaneous monitoring of M-proteins, t-Abs, and polyclonal Ig-titers using an untargeted mass spectrometry assay, offering a comprehensive view of therapy response. Methods: Sera collected between 2013 and 2024 from four patients and cerebrospinal fluid (CSF) from one patient who received various t-Abs were analyzed with MS-MRD. M-protein sequences were obtained with a multi-enzyme de novo protein sequencing approach. Unique peptides for M-proteins and t-Abs were selected based on linearity, sensitivity, and slope coefficient in serial dilutions. Ig constant regions were monitored using isotype-specific peptides. Results: The MS-MRD multiplex analysis provided detailed information on drug concentrations and therapy response kinetics. For example, in two patients with refractory disease over five lines of therapy, the MS-MRD analysis showed that the deepest responses were achieved with bispecific t-Ab (teclistamab) treatment. M-protein and t-Ab were also detectable in the CSF of one patient with MS-MRD. Conclusions: This proof-of-concept study shows that the multiplex monitoring of the M-protein, any t-Ab combination, and all Ig-isotypes within one mass spectrometry run is feasible and provides unique insight into therapy response kinetics. [ABSTRACT FROM AUTHOR]

Introduction: Posaconazole is recommended for prophylaxis in pediatric immunocompromised patients. Due to its variability in bioavailability and drug-to-drug interactions, EBMT recommends regimens based on therapeutic drug monitoring (TDM). Materials and methods: In total, 171 oncohematological pediatric patients on posaconazole prophylaxis were included. Full pharmacokinetic posaconazole profiles were assessed in 51 children. The efficacy and safety of posaconazole was evaluated by measuring the drug concentration, with dose modification attempted in patients with suboptimal results. The influence of modifying factors on the posaconazole plasma concentration (PPC) was investigated. Results: An insufficient PPC was the main issue, but no significant increase in prophylaxis failure was reported. The modification of the dosage resulted in the optimization of PPC in 50% of patients. No significant correlation between age, gender, diagnosis or the posaconazole dosage and the PPC was found. HCT, total parenteral nutrition and diarrhea were associated with a lower PPC. Hypoalbuminemia was related to both higher and lower PPC. The concomitant administration of specified drugs significantly impacted the PPC. Conclusions: TDM allows the identification of patients receiving non-optimal treatment and offers an opportunity to improve the efficacy and safety of the therapy. However, further research involving larger patient groups and longer observation periods are needed to determine the optimal dosing and target PPC in pediatric patients. [ABSTRACT FROM AUTHOR]

In recent years, many population pharmacokinetic (popPK) models have been developed for echinocandins to better understand the pharmacokinetics (PK) of these antifungals. This comprehensive review aimed to summarize popPK models of echinocandins (micafungin, caspofungin, anidulafungin, and rezafungin), by focusing on dosage optimization to maximize the probability of attaining the PK/PD target proposed in special populations. A search in PubMed, Embase, Web of Science, and Scopus, supplemented by the bibliography of relevant articles, was conducted from inception to March 2024, including both observational and prospective trials. A total of 1126 articles were identified, 47 of them were included in the review (22 for micafungin, 13 for caspofungin, 9 for anidulafungin, and 3 for rezafungin). A two-compartment model was more frequently used to describe the PK parameters of echinocandin (78.7% of developed models), although more complex structural models with three and four compartments have also been developed. The covariates to estimate the PK parameters such as clearance (CL) and volume of distribution (Vd) differed between models. Weight total (WT) was the most frequently reported to be a significant predictor for both parameters, especially for estimating the CL in pediatrics. The PD parameter most widely reported assessing the drug exposure–efficacy relationship was the area under the concentration–time curve to minimum inhibitory concentration (MIC) ratio (AUC0–24/MIC) with different targets proposed for each echinocandin. In certain populations such as patients that are critically ill, obese, receiving extracorporeal membrane oxygenation (ECMO) and/or continuous renal replacement therapy (CRRT), or pediatric patients and/or patients with cancer or that are immunocompromised, the fixed dosing strategies recommended in the drug prescribing information may not reach the PK/PD target. For these populations, different strategies have been proposed, such as a dosing regimen based on body weight or increasing the loading and/or maintenance dose. Despite echinocandins' favorable safety profile and predictable PK, certain groups at risk of suboptimal drug exposure can benefit from therapeutic drug monitoring (TDM) to prevent clinical failures. Numerous popPK models of echinocandins have been developed. However, an external validation of the suggested dosing regimens in conjunction with an analysis of population subgroups should be conducted before implementing a popPK model in clinical practice. [ABSTRACT FROM AUTHOR]

Population pharmacokinetic (popPK) models are an essential tool when implementing therapeutic drug monitoring (TDM) and to overcome dosing challenges in neonates in clinical practice. Since vancomycin, gentamicin, and amikacin are among the most prescribed antibiotics for the neonatal population, we aimed to characterize the popPK models of these antibiotics and the covariates that may influence the pharmacokinetic parameters in neonates and infants with no previous pathologies. We searched the PubMed, Embase, Web of Science, and Scopus databases and the bibliographies of relevant articles from inception to the beginning of February 2024. The search identified 2064 articles, of which 68 met the inclusion criteria (34 for vancomycin, 21 for gentamicin, 13 for amikacin). A one-compartment popPK model was more frequently used to describe the pharmacokinetics of the three antibiotics (91.2% vancomycin, 76.9% gentamicin, 57.1% amikacin). Pharmacokinetic parameter (mean ± standard deviation) values calculated for a "typical" neonate weighing 3 kg were as follows: clearance (CL) 0.34 ± 0.80 L/h for vancomycin, 0.27 ± 0.49 L/h for gentamicin, and 0.19 ± 0.07 L/h for amikacin; volume of distribution (Vd): 1.75 ± 0.65 L for vancomycin, 1.54 ± 0.53 L for gentamicin, and 1.67 ± 0.27 L for amikacin for one-compartment models. Total body weight, postmenstrual age, and serum creatinine were common predictors (covariates) for describing the variability in CL, whereas only total body weight predominated for Vd. A single universal popPK model for each of the antibiotics reviewed cannot be implemented in the neonatal population because of the significant variability between them. Body weight, renal function, and postmenstrual age are important predictors of CL in the three antibiotics, and total body weight for Vd. TDM represents an essential tool in this population, not only to avoid toxicity but to attain the desired pharmacokinetic/pharmacodynamic index. The characteristics of the neonatal population, coupled with the lack of prospective studies and external validation of most models, indicate a need to continue investigating the pharmacokinetics of these antibiotics in neonates. [ABSTRACT FROM AUTHOR]

Background: Therapeutic drug monitoring (TDM) and target concentration intervention (TCI) represent significant advancements in individualized medicine, aiming to tailor dosages based on patient-specific characteristics. These approaches account for intra- and inter-individual physiological and clinical variability, with the goal of improving target attainment and clinical remission while reducing treatment failure and adverse effects. Objectives: The objective is to assess and enhance the current body of randomized controlled trials (RCTs) that have investigated alternative personalized dosing strategies, such as TDM and TCI, in terms of their efficacy and safety for individualized antimicrobial dosing in pediatric populations. Only studies that compared different dosing regimens and reported plasma concentrations were included in the analysis. Methods: Databases such as MEDLINE, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials were searched until January 3rd, 2024. Only published, peer-reviewed RCTs were considered for inclusion. The study focused on human subjects aged < 18 years who were receiving an antimicrobial drug. The interventions compared experimental dosing versus standard dosing with TDM or TCI. The risk of bias was assessed using version 2 of the Cochrane risk-of-bias tool for randomized trials. The primary outcome was the attainment of target concentrations, while secondary outcomes included adverse effects, clinical remission, and treatment failure. Data synthesis was performed using the restricted maximum likelihood method, and the risk ratio (RR) was used as the measure of effect size. Results: Only 11 TDM-based RCTs were included in the study [experimental vs standard doses: 592 (51.3%) patients vs 563 (48.7%) patients]. Experimental dose was significantly associated with improvement in target attainment (RR 1.2587, OR 1.0717–1.4786; p = 0.0051). However, experimental antimicrobial dose optimization was non-significantly associated with a numerical decrease in treatment failure (RR 0.8966, OR 0.7749–1.0374; p = 0.1424). In addition, it was not significant associated with higher adverse effects [RR 1.3408, odds ratio (OR) 0.1783–10.0825; p = 0.7757] and clinical remission rates (RR 4.0589, OR 0.2494–66.0558; p = 0.3250). Conclusions: This meta-analysis showed that only target attainment using TDM was significantly improved in pediatric patients treated with experimental doses of antimicrobials compared to standard doses. Larger TCI-focused RCTs are needed to significantly improve treatment failure, adverse effects, and clinical remission. [ABSTRACT FROM AUTHOR]

Epidural analgesia is an effective way to manage pain for labor and delivery, surgery, trauma, cancer, and neuropathic pain. It involves the administration of local anesthetics and/or opioids into the epidural space. To ensure its efficacy and safety, nurses must understand the basic anatomy and pharmacology of epidural analgesia, considerations when monitoring patients, and identify its adverse reactions. To ensure the efficacy and safety of epidural analgesia, nurses must understand the basic anatomy and pharmacology of epidural analgesia, know the considerations when monitoring patients, and identify its adverse reactions. [ABSTRACT FROM AUTHOR]

Objectives The co-resistance between bedaquiline and clofazimine raises significant concerns, as they are commonly co-administered as core drugs in drug-resistant TB regimens. The present study aimed to monitor drug resistance-associated gene mutations and the phenotypic change in Mycobacterium tuberculosis (Mtb) under a stepwise drug resistance induction in vitro using bedaquiline, clofazimine or combined drugs. Methods Drug-resistant Mtb strains were gradually induced in vitro on a drug-containing solid medium with a 2-fold increasing concentration of bedaquiline, clofazimine and their combination. The MIC of the induced drug-resistant Mtb strains was determined. The drug resistance-associated genes, including Rv0678 , Rv1979c , atpE and pepQ , were sequenced and analysed. Results Unlike exposure to bedaquiline alone or the combination of these two drugs, clofazimine alone resulted in drug resistance gene mutations occurring later, specifically in the fourth round of induction as opposed to the second round of induction. Besides, nucleotide deletion or insertion in Rv0678 was the main mutation type for induction under the two-drug combination, while single-nucleotide polymorphisms (SNPs) in Rv0678 were the major mutation types when induced by bedaquiline or clofazimine alone. Rv0678 mutation happened at a relatively lower bedaquiline concentration exposure alone, while atpE mutation occurred at a higher bedaquiline concentration. Regardless of the drug exposure manner, a strong correlation between bedaquiline MICs and clofazimine MICs was observed in all drug resistance strains. Conclusions Combined exposure to bedaquiline and clofazimine developed Rv0678 mutation as early as exposure to bedaquiline alone. However, rather than SNPs, deletion and insertion were the dominant mutation types in dual-drug exposure strain. [ABSTRACT FROM AUTHOR]

Background The emergence of β-lactamase-producing bacteria has led to the use of β-lactam (BL) antibiotic and β-lactamase inhibitor (BLI) drug combinations. Despite therapeutic drug monitoring (TDM) being endorsed for BLs, the impact of TDM on BLIs remains unclear. Objectives Evaluate whether BLIs are available in effective exposures at the site of infection and assess if TDM of BLIs could be of interest. Methods Population pharmacokinetic models for 9 BL and BLI compounds were used to simulate drug concentrations at infection sites following EMA-approved dose regimens, considering plasma protein binding and tissue penetration. Predicted target site concentrations were used for probability of target attainment (PTA) analysis. Results Using EUCAST targets, satisfactory (≥90%) PTA was observed for BLs in patients with typical renal clearance (CrCL of 80 mL/min) across various sites of infection. However, results varied for BLIs. Avibactam achieved satisfactory PTA only in plasma, with reduced PTAs in abdomen (78%), lung (73%) and prostate (23%). Similarly, tazobactam resulted in unsatisfactory PTAs in intra-abdominal infections (79%), urinary tract infections (64%) and prostatitis (34%). Imipenem-relebactam and meropenem-vaborbactam achieved overall satisfactory PTAs, except in prostatitis and high-MIC infections for the latter combination. Conclusions This study highlights the risk of solely relying on TDM of BLs, as this can indicate acceptable exposures of the BL while the BLI concentration, and consequently the combination, can result in suboptimal performance in terms of bacterial killing. Thus, dose adjustments also based on plasma concentration measurements of BLIs, in particular for avibactam and tazobactam, can be valuable in clinical practice to obtain effective exposures at the target site. [ABSTRACT FROM AUTHOR]

Mycophenolic Acid (MPA) is the most used anti-proliferative in lung transplantation, but its pharmacokinetic (PK) variability has precluded therapeutic drug monitoring. Both genetic and clinical factors have been implicated in MPA variability. This study aimed to integrate genetic and clinical factors with PK measurements to quantify MPA exposure. We performed 12-hour pharmacokinetic analysis on 60 adult lung transplant recipients maintained on MPA for immunosuppression. We genotyped a SLCO1B3 polymorphisms previously associated MPA metabolism and collected relevant clinical data. We calculated area under the curve (AUC 0–12) and performed univariate linear regression analysis to evaluate its association with genetic, clinical, and pharmacokinetic variables. We performed lasso regression analysis to create final AUC estimation tools. PK-only measurements obtained 2, 3, and 8 hours after MPA administration (C 2 , C 3, and C 8) were strongly associated with MPA AUC 0–12 (R 2 67%, 67% and 68% respectively). Clinical and genetic factors associated with MPA AUC 0–12 included the MPA dose (p = 0.001), transplant diagnosis (p = 0.015), SLCO1B3 genotype (p = 0.049), and body surface area (p = 0.050). The best integrated single-sampling strategy included C 2 and achieved an R2 value of 80%. The best integrated limited-sampling strategy included C 0 , C 0.25 , and C 2 and achieved an R2 value of 90%. An integrated limited sampling strategy (LSS) for MPA allows increased accuracy in prediction of MPA AUC 0–12 compared to PK-only modeling. Validation of this model will allow for clinically feasible MPA therapeutic drug monitoring and help advance precision management of MPA. [ABSTRACT FROM AUTHOR]

Inflammation is an essential physiological defence mechanism, but prolonged or excessive inflammation can cause disease. Indeed, unresolved systemic and adipose tissue inflammation drives obesity-related cardiovascular disease and type 2 diabetes mellitus. Drugs targeting pro-inflammatory cytokine pathways or inflammasome activation have been approved for clinical use for the past two decades. However, potentially serious adverse effects, such as drug-induced weight gain and increased susceptibility to infections, prevented their wider clinical implementation. Furthermore, these drugs do not modulate the resolution phase of inflammation. This phase is an active process orchestrated by specialized pro-resolving mediators, such as lipoxins, and other endogenous resolution mechanisms. Pro-resolving mediators mitigate inflammation and development of obesity-related disease, for instance, alleviating insulin resistance and atherosclerosis in experimental disease models, so mechanisms to modulate their activity are, therefore, of great therapeutic interest. Here, we review current clinical attempts to either target pro-inflammatory mediators (IL-1β, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, tumour necrosis factor (TNF) and IL-6) or utilize endogenous resolution pathways to reduce obesity-related inflammation and improve cardiometabolic outcomes. A remaining challenge in the field is to establish more precise biomarkers that can differentiate between acute and chronic inflammation and to assess the functionality of individual leukocyte populations. Such advancements would improve the monitoring of drug effects and support personalized treatment strategies that battle obesity-related inflammation and cardiometabolic disease. This Review discusses translational attempts to mitigate the inflammation that drives obesity-related cardiometabolic diseases. The Review also focuses on mechanisms that control inflammatory cascades, either through traditional anti-inflammatory drugs or via the specialized pro-resolving mediators that actively control the resolution of inflammation. Key points: Chronic unresolved systemic and adipose tissue inflammation drives obesity-related cardiometabolic disease. Drugs targeting pro-inflammatory cytokines, or inflammasome activation, are approved for clinical use but can elicit serious adverse effects (such as weight gain and increased susceptibility to infections), hampering their clinical implementation. The resolution phase of inflammation is an active process regulated by specialized pro-resolving mediators. These mediators mitigate obesity-related inflammation and systemic disease in experimental models and are of therapeutic interest. The field lacks biomarkers that can differentiate between acute and chronic inflammation and assess the functionality of individual leukocyte populations, which would improve personalized treatment strategies and support drug monitoring. [ABSTRACT FROM AUTHOR]

Purpose: The metabolism of tamoxifen is influenced by various cytochrome p450 enzymes, including CYP2D6 and CYP2C19, leading to variations in the levels of endoxifen, even with the same tamoxifen dose. However, the clinical significance of endoxifen for the prognosis of breast cancer patients remains controversial. This study aimed to elucidate the relevance of endoxifen level to recurrence-free survival censored with tamoxifen discontinuation (RFSt), representing the RFS for tamoxifen itself, of breast cancer patients and determine a suitable cutoff for prognostication. Materials and Methods: The study included 478 breast cancer patients. Tamoxifen and its metabolites, including endoxifen, were measured using liquid chromatography-tandem mass spectrometry. An optimal cutoff was determined with maximally selected rank statistics. Survival analysis and Cox regression were conducted based on this cutoff. Results: An endoxifen level of 21.00 ng/mL was the optimal cutoff for prognostication. Survival analysis revealed a statistically significant difference in RFSt between the low endoxifen group (≤ 21.00 ng/mL) and the high endoxifen group (> 21.00 ng/mL) (log-rank test, p=0.032). The 10-year probability of RFSt was 83.2% (95% confidence interval [CI], 77.0 to 89.9) and 88.3% (95% CI, 83.3 to 93.5) in the low and high endoxifen groups, respectively. Multivariable Cox proportional hazards regression indicated endoxifen concentration as a significant factor associated with prognosis. Conclusion: Endoxifen could serve as a marker for appropriate tamoxifen treatment with a cutoff of 21.00 ng/mL. Based on this cutoff, therapeutic drug monitoring would benefit patients displaying suboptimal endoxifen concentrations. [ABSTRACT FROM AUTHOR]

Background: Cost-utility analyses (CUAs) increasingly use models to predict long-term outcomes and translate trial data to real-world settings. Model structure uncertainty affects these predictions. This study compares pharmacometric against traditional pharmacoeconomic model evaluations for CUAs of sunitinib in gastrointestinal stromal tumors (GIST). Methods: A two-arm trial comparing sunitinib 37.5 mg daily with no treatment was simulated using a pharmacometric-based pharmacoeconomic model framework. Overall, four existing models [time-to-event (TTE) and Markov models] were re-estimated to the survival data and linked to logistic regression models describing the toxicity data [neutropenia, thrombocytopenia, hypertension, fatigue, and hand-foot syndrome (HFS)] to create traditional pharmacoeconomic model frameworks. All five frameworks were used to simulate clinical outcomes and sunitinib treatment costs, including a therapeutic drug monitoring (TDM) scenario. Results: The pharmacometric model framework predicted that sunitinib treatment costs an additional 142,756 euros per quality adjusted life year (QALY) compared with no treatment, with deviations − 21.2% (discrete Markov), − 15.1% (continuous Markov), + 7.2% (TTE Weibull), and + 39.6% (TTE exponential) from the traditional model frameworks. The pharmacometric framework captured the change in toxicity over treatment cycles (e.g., increased HFS incidence until cycle 4 with a decrease thereafter), a pattern not observed in the pharmacoeconomic frameworks (e.g., stable HFS incidence over all treatment cycles). Furthermore, the pharmacoeconomic frameworks excessively forecasted the percentage of patients encountering subtherapeutic concentrations of sunitinib over the course of time (pharmacoeconomic: 24.6% at cycle 2 to 98.7% at cycle 16, versus pharmacometric: 13.7% at cycle 2 to 34.1% at cycle 16). Conclusions: Model structure significantly influences CUA predictions. The pharmacometric-based model framework more closely represented real-world toxicity trends and drug exposure changes. The relevance of these findings depends on the specific question a CUA seeks to address. [ABSTRACT FROM AUTHOR]

Recent advances in therapeutic drug monitoring (TDM) and model-informed precision dosing (MIPD) are reshaping treatment strategies for inflammatory bowel diseases (IBDs). MIPD uses pharmacokinetic/pharmacodynamic (PK/PD) models that integrate patient data to optimize drug dosing. Recent studies highlight the significance of therapeutic thresholds in guiding dose adjustments, aiming to improve patient outcomes. Emerging technologies such as point-of-care assays and self-sampling devices facilitate more precise and real-time monitoring of drug levels. Effective MIPD in prospective TDM will require enhancement of models with biomarker data and facilitate deeper understanding of exposure–response relationships. Therapeutic drug monitoring (TDM) for biologic therapies in inflammatory bowel disease (IBD) primarily aims to optimize dosing. However, several unmet needs remain. These include the identification of optimal drug concentrations, accounting for variability in pharmacokinetics (PK) and pharmacodynamics (PD), and the frequent delays between sampling and clinical decision-making. Recent technical advances, such as population PK/PD modeling and model-informed precision dosing (MIPD) tools developed from such models, as well as point-of-care (POC) and self-sampling assays and novel software programs, offer potential solutions. Successful implementation of these innovations may help to establish MIPD for patients with IBD. This would enable personalized dosing, advancing a one-size-fits-all approach to TDM that currently is inadequate to fulfill the needs for every patient with IBD. [ABSTRACT FROM AUTHOR]

Purpose: The role of therapeutic drug monitoring (TDM) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients receiving letermovir has not yet been clarified. This study is to explore letermovir trough concentration (Cmin) correlation with its clinical efficacy and adverse events, and factors affecting its plasma concentrations. Methods: A prospective, non-interventional study was performed in allo-HSCT recipients receiving letermovir prophylaxis. Plasma concentrations were determined using high-performance liquid chromatography-tandem mass spectrometry. Data analysis was performed using logistic regression, linear regression, and classification and regression tree (CART) models. Results: 701 trough concentrations from 71 recipients were included, uncovering pronounced intra- and inter-individual variability in letermovir Cmin. During 24-week follow-up, CMV infection incidence was 16.4%. A significant correlation was identified between letermovir Cmin and its clinical efficacy, and the CART model showed an increased risk of CMV infection when Cmin ≤ 2731 ng/mL. However, no clear correlation was found between Cmin and adverse events. Gastrointestinal graft-versus-host disease, cyclosporine Cmin, gender, and concomitant medications, including mycophenolate mofetil, ondansetron, caspofungin, and methylprednisolone, may impact letermovir Cmin. Additionally, coadministration with cyclosporine injection significantly decreased median letermovir Cmin compared with cyclosporine capsules (2311 vs. 3386 ng/mL). Moreover, with the extension of time post-transplant, trough concentrations of both cyclosporine and letermovir significantly decreased. Conclusion: TDM for letermovir may be beneficial in allo-HSCT recipients considering the variability in letermovir Cmin and its correlation with clinical efficacy. Moreover, drug interactions and the effects of changes in cyclosporine dosage forms or concentrations require careful monitoring for their effect on letermovir Cmin. [ABSTRACT FROM AUTHOR]

Background: Propofol, a commonly used agent for short- and long-term sedation, is associated with acute pancreatitis. The main indirect mechanism of propofol-associated acute pancreatitis is by inducing hypertriglyceridemia. Patients with severe coronavirus disease 2019 (COVID-19) pneumonia often require prolonged mechanical ventilation and sedation. We examined the incidence rate of acute pancreatitis among critically ill adults with COVID-19 pneumonia on mechanical ventilation receiving propofol. In addition, we attempted to determine cutoff levels of serum triglycerides and doses of propofol that are predictive of propofol-associated acute pancreatitis. Methods: This was a multicenter retrospective cohort study using a large dataset of hospitalized patients with COVID-19. The collected data included the number of days on propofol, cumulative doses of propofol, peak levels of serum triglycerides, serum lipase levels, and abdominal imaging findings. We used receiver-operating characteristic analysis in conjunction with Youden's index to identify the optimal thresholds for propofol administration parameters and levels of triglycerides that would provide maximal sensitivity and specificity for predicting acute pancreatitis. Results: Out of 499 critically ill patients with COVID-19 pneumonia, 154 met the inclusion criteria. Six (4%) patients had suspected acute pancreatitis based on elevated serum lipase levels. Cutoff values greater than 688 mg/dL for peak level of triglycerides, 4.5 days on propofol, 3007 mg/day for average daily propofol dose, and 24 113 mg for cumulative propofol dose were associated with high risk of suspected acute pancreatitis. The negative predictive values for suspected acute pancreatitis using these cutoffs ranged from 98% to 100%. Conclusions: Propofol use in critically ill COVID-19 patients is associated with a low incidence rate of acute pancreatitis. We identified cutoff values for serum triglycerides and cumulative propofol dose that are linked to higher risk of propofol-associated pancreatitis. More research is needed to examine the true incidence of propofol-associated pancreatitis and help develop optimal cutoff values for certain parameters to help guide safe propofol administration. [ABSTRACT FROM AUTHOR]

The document discusses simplified preanalytical laboratory procedures for therapeutic drug monitoring (TDM) in patients treated with high-dose methotrexate (HD-MTX) and glucarpidase. High-dose methotrexate therapy is used in various malignancies, but can occasionally cause acute crystal nephropathy. Glucarpidase is an enzyme that rapidly cleaves methotrexate and its metabolites, and therapeutic drug monitoring is essential for patients treated with glucarpidase. The study found that preanalytical blood sample processing without acidification is sufficient for TDM, but storage conditions can impact the quantification of methotrexate and its metabolites, highlighting the importance of proper sample storage for clinical decision-making. [Extracted from the article]