Therapeutic Drug Monitoring最新文献

Background: Digoxin is a cardioactive drug with a narrow therapeutic range, making therapeutic drug monitoring (TDM) essential in clinical practice. We aimed to establish an ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for the simultaneous determination of digoxin, deslanoside, and three cardiac glycosides from Qiliqiangxin capsule (periplogenin, periplocymarin, and periplocin) in human plasma, and to identify their interference in digoxin TDM by comparison with the enzyme multiplied immunoassay technique (EMIT).

Methods: Chromatographic separation was performed on a reverse-phase column with gradient elution. Mass spectrometry detection was performed using an electrospray ionization source and multiple reaction monitoring mode. Sample pretreatment was conducted using liquid-liquid extraction.

Results: The five analytes exhibited good linearity across the range of 0.05-10 ng/mL. Intra- and interbatch accuracy ranged from 90.6% to 105.1%, with imprecision below 10.6%. Application of this method to 314 TDM samples showed that digoxin concentrations measured using UHPLC-MS/MS and EMIT were consistent (r = 0.972) for patients taking digoxin alone. However, owing to cross-reactivity, EMIT overestimated digoxin concentrations in patients receiving only Qiliqiangxin capsule or deslanoside compared with UHPLC-MS/MS.

Conclusions: The developed UHPLC-MS/MS method was highly sensitive and time-efficient, making it a reliable tool for digoxin TDM and identifying interference from Qiliqiangxin capsule and deslanoside.

Background: Guanfacine, an enteral α2-adrenergic and imidazoline receptor agonist, has occasionally been described in critical care as an adjunctive agent for the management of delirium and suspected dexmedetomidine withdrawal. However, its pharmacokinetic behavior during venovenous extracorporeal membrane oxygenation (VV ECMO) combined with continuous venovenous hemofiltration (CVVH) has not been defined.

Methods: A 64-year-old man with severe COVID-19 pneumonia developed refractory hypoxemia, requiring VV ECMO and CVVH for multiorgan support. Enteral guanfacine 7 mg/d was initiated on day 14 to transition from dexmedetomidine sedation.

Results: Steady-state trough plasma and ultrafiltrate guanfacine concentrations of 3.2 and 0.5 ng/mL, respectively, were obtained on day 24, yielding a sieving coefficient of 0.16 and convective clearance of 0.267 mL/min. ECMO adsorption was negligible based on expected pharmacokinetic concentrations. The patient was decannulated from ECMO on day 30, and guanfacine was successfully tapered over 7 days without withdrawal symptoms occurring.

Conclusions: In this patient, high-dose guanfacine achieved predicted plasma concentrations during concurrent VV ECMO and CVVH, with minimal extracorporeal clearance or circuit sequestration. These findings suggest that standard dosing is appropriate in similar patients and support the use of guanfacine as a viable transition agent during dexmedetomidine weaning. Prospective pharmacokinetic studies in ECMO-supported patients are warranted.

Objectives: To determine how certolizumab pegol (CZP) dose and dose adjustments influence CZP plasma trough levels to facilitate therapeutic drug monitoring of CZP.

Methods: The effect of CZP dose and dose adjustments on CZP plasma trough levels was evaluated post hoc using longitudinal data from a 52-week randomized phase III trial (RAPID 1) and its open-label extension trial. Patients with active rheumatoid arthritis treated with methotrexate for ≥6 months were randomized to CZP 200 mg, 400 mg, or placebo every other week (EOW). Patients in the extension trial were initially treated with CZP 400 mg EOW, then reduced to 200 mg EOW after ≥6 months.

Results: Of 982 randomized patients, 846 patients entered the open-label extension trial. Median (interquartile range) plasma CZP concentrations after 12 weeks of treatment were 21.3 mg/L (14.7, 27.7) in the 200-mg group and 38.3 mg/L (29.2, 63.8) in the 400-mg group and increased from 18.3 (12.4, 26.5) to 43.4 (26.8, 63.3) mg/L after dose escalation from 200 to 400 mg EOW. Following CZP dose reduction from 400 mg to 200 mg, median CZP levels decreased from 36.1 (24.9, 49.0) to 17.2 (11.5, 23.1) mg/L.

Conclusions: CZP plasma concentrations were influenced by both dose and dose adjustment in a predictable manner, with median plasma levels twice as high in the 400-mg group than in the 200-mg group, with a 2-fold increase after the dose increase from 200 to 400 mg. This facilitates the development of algorithms for therapeutic drug monitoring of CZP.

Background: The rise of nonfentanyl synthetic opioids such as brorphine highlights the dynamic evolution of illicit opioid markets and the persistent toxicological and public health risks they pose.

Methods: Studies reporting the pharmacology, toxicology, and analytical detection of brorphine and its analogues were identified through systematic searches of PubMed and Scopus databases. Additional data from official international organizations' early-warning platforms were also included.

Results: Brorphine acts as a potent μ-opioid receptor agonist with preclinical evidence of strong antinociceptive activity, respiratory depression, and abuse potential. Since 2019, it has been increasingly identified in forensic casework, frequently in combination with fentanyl or benzodiazepines, and implicated in multiple nonfatal and fatal intoxications. Structurally related analogues, including halogenated derivatives and "orphine-type" compounds, whose pharmacological properties and toxicological profiles are not well understood, have emerged. Although several liquid chromatography coupled with mass spectrometry-based methods exist for brorphine detection, no validated analytical workflows or certified reference materials are currently available for its analogues, limiting comprehensive monitoring and biomonitoring capacity.

Conclusions: The rapid spread of brorphine and its analogues underscores the ongoing transition from fentanyl derivatives toward novel nonfentanyl μ-opioid receptor agonists. These substances pose significant analytical and toxicological challenges and require increased international surveillance, improved laboratory capabilities, and coordinated public health responses to reduce their impact.

Background: Scedosporium spp. typically infect the lungs and can disseminate to various tissues, including the central nervous system (CNS). Voriconazole and terbinafine are both used to treat scedosporiosis. While voriconazole has been reported to have good CNS permeability, the permeability of terbinafine in humans remains unclear.

Methods: The authors describe a case of Scedosporium apiospermum infection with brain abscesses in a lung transplant recipient treated with voriconazole and terbinafine. Drug concentrations were measured in the biopsied brain abscess, the surrounding normal cerebrum, serum, and cerebrospinal fluid (CSF). Brain-to-serum and CSF-to-serum partition coefficients for each drug were calculated based on serum concentrations estimated at the time of abscess biopsy and lumbar puncture using population pharmacokinetic models.

Results: Trough serum concentrations of voriconazole and terbinafine were 6.28 mcg/mL and 0.41 mcg/mL, respectively. Seven hours after administration, the concentrations in cerebrum were 5.65 mcg/mL and 0.85 mcg/mL, respectively, and those in brain abscess were 4.05 mcg/mL and 1.06 mcg/mL, respectively. The estimated brain-to-serum partition coefficients were 0.730 for voriconazole and 0.553 for terbinafine, indicating substantial penetration of both drugs into the infected tissue. The brain abscess size decreased in this case, suggesting a therapeutic antifungal effect of these agents. However, the measured CSF concentrations at 5 hours postdose were 2.69 mcg/mL for voriconazole and <0.002 mcg/mL for terbinafine. The CSF-to-serum partition coefficients were 0.365 for voriconazole and <5.64 × 10 -4 for terbinafine, indicating poor CSF permeability of terbinafine.

Conclusions: These findings suggest that terbinafine has the potential to treat fungal infections within the brain, but may be less effective for CSF infections. Further studies are warranted to clarify incorporation of these agents into CNS infection treatment strategies.

Background: Over the past decade, cystic fibrosis transmembrane conductance regulator (CFTR) modulators have revolutionized the treatment of cystic fibrosis. Currently, 4 modulators are approved for clinical use: ivacaftor, lumacaftor, tezacaftor, and elexacaftor. Despite their clinical benefits, these drugs show significant pharmacokinetic variability and interindividual differences in therapeutic response. This review aimed to evaluate the available evidence supporting therapeutic drug monitoring of CFTR modulators and to highlight knowledge gaps that may limit its clinical implementation.

Methods: A comprehensive literature review was conducted, focusing on elexacaftor, tezacaftor, and ivacaftor. Bioanalytical methods developed for quantifying these compounds in biological fluids were systematically analyzed, and reported drug concentration ranges were summarized.

Results: Multiple analytical methods have been described for the quantification of CFTR modulators, showing varying degrees of sensitivity and suitability for clinical application. Reported plasma concentration ranges confirm a high degree of interindividual pharmacokinetic variability. However, the relationship between drug exposure, therapeutic efficacy, and safety outcomes remains only partially defined.

Conclusions: Although CFTR modulators meet many of the established criteria for therapeutic drug monitoring, critical gaps persist, particularly regarding exposure-response relationships and optimal sampling strategies. Addressing these issues will be essential to establish therapeutic drug monitoring as a reliable tool for personalizing CFTR modulator therapy in patients with cystic fibrosis.

Background: Ampicillin-sulbactam is the first-line treatment for pneumonia, aspiration pneumonia, and infections caused by Acinetobacter baumannii . Several population pharmacokinetic (PK) studies have evaluated the intravenous administration of ampicillin-sulbactam in adults. This systematic review aimed to compare published PK models and identify covariates influencing ampicillin-sulbactam PKs.

Methods: A comprehensive literature search was conducted using PubMed and Scopus from inception to March 2025. Relevant articles from reference lists were also incorporated. This review included all population PK models of ampicillin-sulbactam administered intravenously in adult patients with various health conditions.

Results: Five studies were reviewed, using a two-compartment model for ampicillin-sulbactam. The PK profiles of ampicillin and sulbactam were found to be similar, with comparable CL and V d across all selected studies. Ampicillin clearance ranged from 5.58 to 11.03 L/h, whereas sulbactam clearance ranged from 4.79 to 10.50 L/h. The volume of distribution varied from 11.78 to 19.12 L for ampicillin and from 13.89 to 16.77 L for sulbactam. Interindividual variability of ampicillin-sulbactam PK parameters varied across the included studies. Creatinine clearance (CLcr), serum creatinine (SCr), body surface area, body weight, and heart failure were found to be significant covariates affecting the PK parameters.

Conclusions: Ampicillin-sulbactam clearance is primarily influenced by renal function (CLcr and SCr) and disease status. None of the studies performed external validation of the developed PK model. This review highlights the PK variability of ampicillin-sulbactam and the need for further research to refine dosing strategies and improve model reliability for clinical application.

Background: Tuberculosis (TB) treatment relies on a prolonged first-line antibiotic regimen, including isoniazid, rifampicin (RF), ethambutol (EMB), and pyrazinamide.Pharmacogenetics plays a crucial role in optimizing TB treatment by addressing individual variability in drug metabolism and responses. Genetic polymorphisms can significantly affect pharmacokinetics and therapeutic outcomes. The aim of this review was to explore the role of pharmacogenetics in first-line antibiotics used to treat TB.

Methods: We reviewed the literature using PubMed, Scopus, Web of Science, and the Cochrane Library, focusing on articles published in the last 10 years (from December 2014 to December 2024) on the pharmacogenetics of first-line anti-TB drugs. Only English-language studies involving human subjects were included, prioritizing those investigating genetic variants that affect drug bioavailability.

Results: In this study, 33 manuscripts were included.N-acetyltransferase 2 Single-nucleotide polymorphisms were associated with different isoniazid acetylation rates, which affect toxicity and efficacy. Genetic variations in CYP2E1 , GSTM1 , and MnSOD also contribute to hepatotoxicity.For RF, variants in SLCO1B1 , ABCB1 , PXR , CAR , CES1 , and CES2 genes were related to variability in drug absorption, metabolism, and clearance, highlighting the need for personalized dosing strategies. Notably, SLCO1B1 rs4149056 polymorphism is associated with decreased OATP1B1 RF transport activity, potentially leading to increased plasma exposure, whereas other polymorphisms modulate drug exposure and clearance rates. In addition, sex, body weight, and genotype influenced RF pharmacokinetics, suggesting the need for tailored dosing recommendations based on patient characteristics.Similarly, variability in EMB pharmacokinetics is associated with CYP1A2 2159, which is related to a 50% reduction in bioavailability, necessitating dose adjustments in patients coinfected with TB and HIV. Some variants of ABCB1 , OATP1B1 , PXR , VDR , CYP24A1 , and CYP27B1 may further modulate the plasma and intracellular concentrations of EMB, thereby influencing drug efficacy.

Conclusions: This review highlights the importance of integrating pharmacogenetic insights into clinical practice to enhance the efficacy of TB treatment, minimize toxicity, and prevent drug resistance. Despite promising evidence, further research and clinical validation are required to implement pharmacogenetics in routine TB management. Future advancements in therapeutic drug monitoring and omics technologies will pave the way for precision medicine in TB therapy.

Background: This review re-evaluates therapeutic drug monitoring (TDM) by comparing the current analytical and subsequent clinical interpretation capabilities of hospital or community medical laboratories with the emerging potential of point-of-care (POC) devices, which could become increasingly utilized in hospital wards, day-hospital units, and outpatient clinic settings.

Methods: A narrative review was conducted to identify publications that best illustrate the current trends in the development of POC TDM.

Results: The latest scientific and technical literature indicates that POC devices for determining drug concentrations in clinical samples are approaching the market. Several technologies are now available to develop portable sensors capable of rapidly returning concentration measurements. Interfacing these methods with artificial intelligence-based pattern recognition may enhance the identification and quantification of drugs. However, once the drug concentration is accurately measured using a portable device, dosage adjustments require consideration of the drug's pharmacokinetics and the patient's characteristics. This is accounted for in the mathematical approaches underlying model-informed precision dosing, which consider inter- and intra-individual variability and provide recommendations for treatment adjustments. These complexities necessitate the use of digital technologies, including graphical interfaces, machine learning approaches, and secure connectivity, to enhance the application of TDM in clinical practice.

Conclusions: Promising emerging technologies have considerable potential to expand TDM to cover a wide range of drugs, making precision medicine accessible to many patients.